Antimalarial compositions and uses thereof

ABSTRACT

Provided herein are compounds, compositions and method of using thereof to treat or prevent malaria.

CROSS-REFERENCE

This application claims the benefit of U.S. Application Ser. No.62/352,455 filed Jun. 20, 2016, all of which is incorporated byreference in its entirety.

BACKGROUND

Malaria is an infectious disease widespread in tropical and sub-tropicalregions of Africa, Asia, and the Americas. In 2010 the World HealthOrganization estimated that there were over 219 million documented casesof malaria and between 660,000 and 1.2 million deaths from the disease(Nayyar, Lancet Infectious Diseases, 12:488-496, 2012).

Malaria is a mosquito-borne infectious disease of humans and otheranimals caused by parasitic protozoans (a group of single-celledmicroorganisms) belonging to the Plasmodium type. Malaria initiallymanifests with mild to severe symptoms including: chills, fever,fatigue, headache, and nausea. Later symptoms include severe anemia, andblood clotting, which can lead to brain damage and other complications,and death. Although five species of Plasmodium (P. falciparum, P. vivax,P. ovale, P. malariae, and P. knowlesi) can infect humans, the majorityof malarial deaths are caused by P. falciparum and P. vivax. Symptomsusually begin ten to fifteen days after being bitten. If not properlytreated, people may have recurrences of the disease months later. Inthose who have recently survived an infection, reinfection usuallycauses milder symptoms. This partial resistance disappears over monthsto years if the person has no continuing exposure to malaria. Fivespecies of the plasmodium parasite can infect humans; the most seriousforms of the disease are caused by Plasmodium falciparum. Malaria causedby Plasmodium vivax, Plasmodium ovale and Plasmodium malariae causesmilder disease in humans that is not generally fatal. A fifth species,Plasmodium knowlesi, is a zoonosis that causes malaria in macaques butcan also infect humans. When a mosquito bites an infected person, asmall amount of blood is taken, which contains malaria parasites. Thesedevelop within the mosquito, and about one week later, when the mosquitotakes its next blood meal, the parasites are injected with themosquito's saliva into the person being bitten. After a period ofbetween two weeks and several months (occasionally years) spent in theliver, the malaria parasites start to multiply within red blood cells,causing symptoms that include fever, and headache. In severe cases thedisease worsens leading to hallucinations, coma, and death.

A wide variety of antimalarial drugs are available to treat malaria. Inthe last 5 years, treatment of P. falciparum infections in endemiccountries has been transformed by the use of combinations of drugscontaining an artemisinin derivative. Severe malaria is treated withintravenous or intramuscular quinine or, increasingly, the artemisininderivative artesunate. Several drugs are also available to preventmalaria in travelers to malaria-endemic countries (prophylaxis).Resistance has developed to several antimalarial drugs, most notablychloroquine.

Malaria transmission can be reduced by preventing mosquito bites bydistribution of inexpensive mosquito nets and insect repellents, or bymosquito-control measures such as spraying insecticides inside housesand draining standing water where mosquitoes lay their eggs.

BRIEF SUMMARY OF THE INVENTION

Described herein are compounds of Formula (IV) or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

-   -   wherein R²¹ is optionally substituted C₃-C₃₀alkenyl or        optionally substituted C₂-C₃₀alkynyl.

In a compound of Formula (IV), R²¹ may be C₃-C₃₀alkenyl. In a compoundof Formula (IV), R²¹ may be C₆-C₃₀alkenyl. In a compound of Formula(IV), R²¹ may be C₆-C₂₅alkenyl. In a compound of Formula (IV), R²¹ maybe C₁₅-C₂₅alkenyl. In a compound of Formula (IV), R²¹ may be

Also described herein is a pharmaceutical composition comprising:

-   -   (i) an oil; and    -   (ii) a compound of Formula (III) or a pharmaceutically        acceptable salt, solvate, or stereoisomer thereof:

wherein:

R¹¹ is a lipophilic moiety.

In the pharmaceutical composition comprising a compound of Formula(III), R¹¹ may be optionally substituted C₁-C₃₀alkyl, optionallysubstituted C₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl. Inthe pharmaceutical composition comprising a compound of Formula (III),R¹¹ may be optionally substituted C₁-C₂₀alkyl, optionally substitutedC₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl. In thepharmaceutical composition comprising a compound of Formula (III), R¹¹may be C₁-C₆alkyl. In the pharmaceutical composition comprising acompound of Formula (III), R¹¹ may be C₇-C₃₀alkyl. In the pharmaceuticalcomposition comprising a compound of Formula (III), R may be R¹¹ is

In the pharmaceutical composition comprising a compound of Formula(III), R¹¹ may be C₂-C₃₀alkenyl. In the pharmaceutical compositioncomprising a compound of Formula (III), R¹¹ may be C₃-C₃₀alkenyl. In thepharmaceutical composition comprising a compound of Formula (III), R¹¹may be C₆-C₃₀alkenyl. In the pharmaceutical composition comprising acompound of Formula (III), R¹¹ may be C₆-C₂₅alkenyl. In thepharmaceutical composition comprising a compound of Formula (III), R¹¹may be C₁₅-C₂₅alkenyl. In the pharmaceutical composition comprising acompound of Formula (III), R¹¹ may be R¹¹ is

In the pharmaceutical composition comprising a compound of Formula(III), the oil may be a vegetable oil. In the pharmaceutical compositioncomprising a compound of Formula (III), the oil may be selected fromcorn oil, peanut oil, sesame oil, olive oil, palm oil, safflower oil,soybean oil, cottonseed oil, rapeseed oil, sunflower oil and mixturesthereof. In the pharmaceutical composition comprising a compound ofFormula (III), the oil may be sesame oil.

In the pharmaceutical composition comprising a compound of Formula(III), the concentration of the compound of Formula (III) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof maybe greater than about 50 mg/mL. In the pharmaceutical compositioncomprising a compound of Formula (III), the concentration of thecompound of Formula (III) or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof may be greater than about 100 mg/mL. Inthe pharmaceutical composition comprising a compound of Formula (III),the concentration of the compound of Formula (III) or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof may be greater thanabout 200 mg/mL.

Described herein are methods for the treatment or prevention of malariain a subject comprising administering to the subject a compound ofFormula (IV) or a pharmaceutical composition comprising a compound ofFormula (III). In the method for the treatment or prevention of malaria,the pharmaceutical composition may be administered by subcutaneous orintramuscular injection. In the method for the treatment or preventionof malaria, the pharmaceutical composition may be effective forsustained or controlled release. In the method for the treatment orprevention of malaria, the compound of Formula (II) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,comprised in the pharmaceutical composition may be administered at adose of about 5 to about 20 mg/day. In the method for the treatment orprevention of malaria, the compound of Formula (III) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,comprised in the pharmaceutical composition may be released from thepharmaceutical composition over a period of a minimum of about 30 daysafter administration. In the method for the treatment or prevention ofmalaria, the compound of Formula (III) or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, comprised in the pharmaceuticalcomposition is released from the pharmaceutical composition at a rateproviding an average concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione inthe blood plasma of said subject of at least about 1000 nM over about 13weeks. In the method for the treatment or prevention of malaria, themethod may further comprise administering an additional antimalarialagent. In the method for the treatment or prevention of malaria, theadditional antimalarial agent is selected from artemisinin, artemisininderivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine,pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine,pyronaridine, halofantrine, or ELQ-300.

Described herein are methods of killing or inhibiting the growth of aPlasmodium species comprising contacting the species with an effectiveamount of a compound of Formula (IV). In the method of killing orinhibiting the growth of a Plasmodium species, the Plasmodium species isPlasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodiummalariae, or Plasmodium knowlesi.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the exposure of ELQ-300 following PO or IM dosing withCompound 2.

FIG. 2A depicts the percent protection following a sporozoite challengeat day 14 following IM administration of Compound 2 (3, 10, and 30mg/kg).

FIG. 2B depicts the exposure of ELQ-300 in mouse following IMadministration of Compound 2 (3, 10, and 30 mg/kg).

FIG. 3A depicts the exposure of ELQ-300 in rat following IMadministration of Compound 2 (3.72 mg/kg in sesame oil).

FIG. 3B depicts the plasma exposure of ELQ-300 and Compound 2 in dogfollowing IM administration of Compound 2 (20 mg/mL, 3% TPGS, 1% HPMC E5suspension).

FIG. 4A depicts the exposure of ELQ-300 in mouse following IMadministration of Compound 2, 4, 8, 9, and 10 (3 mg/kg, 1.5 mg/mL insesame oil).

FIG. 4B depicts the exposure of ELQ-300 in mouse following IMadministration of Compound 12, 13, 14, 16, 17, and 18 (3 mg/kg, 1.5mg/mL in sesame oil).

FIG. 5 depicts the characteristic X-ray diffraction pattern of thecrystalline ELQ-300-Form IA.

FIG. 6 depicts the characteristic X-ray diffraction pattern of thecrystalline ELQ-300-Form IB.

FIG. 7 depicts the characteristic X-ray diffraction pattern of thecrystalline ELQ-300-Form II (first preparation).

FIG. 8 depicts the DSC of the crystalline ELQ-300-Form II (firstpreparation).

FIG. 9 depicts the characteristic X-ray diffraction pattern of thescaled up crystalline ELQ-300-Form II (1^(st) scale up batch).

FIG. 10 depicts the characteristic X-ray diffraction pattern of the2^(nd) scale up batch of crystalline ELQ-300-Form II (2^(nd) scale upbatch).

FIG. 11 depicts the DSC of crystalline ELQ-300-Form II (2^(nd) scale upbatch).

FIG. 12 depicts the characteristic X-ray diffraction pattern of thecrystalline ELQ-300-Form III.

FIG. 13A depicts the DSC of crystalline ELQ-300-Form III.

FIG. 13B depicts the TGA of crystalline ELQ-300-Form III.

FIG. 14 depicts the characteristic X-ray diffraction pattern of thecrystalline ELQ-300-Form IV.

FIG. 15A depicts the DSC of crystalline ELQ-300-Form IV.

FIG. 15B depicts the TGA of crystalline ELQ-300-Form IV.

FIG. 16 depicts the characteristic X-ray diffraction pattern of thecrystalline ELQ-300-Form V.

FIG. 17A depicts the DSC of crystalline ELQ-300-Form V.

FIG. 17B depicts the TGA of crystalline ELQ-300-Form V.

FIG. 18 depicts a comparison in exposure of ELQ-300 following IMadministration of Compound 2 and 13 in sesame oil versus twoELQ-300-Form II suspensions.

FIG. 19A depicts the exposure of ELQ-300 following IM injection of threeELQ-300-Form II suspensions (100 mg/mL Synperonic).

FIG. 19B depicts the exposure of ELQ-300 following IM injection of threeELQ-300-Form II suspensions (100 mg/mL 3% TPGS).

FIG. 20 depicts a comparison in exposure of ELQ-300 following IMadministration of Compound 2 in sesame oil (4 mg/kg) versus twoELQ-300-Form II suspensions (4 mg/kg).

FIG. 21 depicts the exposure of atovaquone following PO or IM dosingwith Compound 27, Compound 28, and atovaquone.

FIG. 22A depicts the percent protection following a sporozoite challengeat day 15 following IM administration of Compound 27 (16.6, 50, and 150mg/kg).

FIG. 22B depicts the exposure of atovaquone in mouse following IMadministration of Compound 27 (16.6, 50, and 150 mg/kg).

FIG. 23 depicts the characteristic X-ray diffraction pattern of thecrystalline atovaquone-Form I.

FIG. 24A depicts the DSC of crystalline atovaquone-Form I.

FIG. 24B depicts the TGA of crystalline atovaquone-Form I.

FIG. 25 depicts the characteristic X-ray diffraction pattern of thecrystalline atovaquone-Form II.

FIG. 26A depicts the DSC of crystalline atovaquone-Form II.

FIG. 26B depicts the TGA of crystalline atovaquone-Form II.

FIG. 27 depicts the exposure of atovaquone following IM injection of twoatovaquone-Form II suspensions (200 mg/mL Synperonic).

FIG. 28 depicts the characteristic X-ray diffraction pattern of thecrystalline pyronaridine-Form I.

FIG. 29A depicts the DSC of crystalline pyronaridine-Form I.

FIG. 29B depicts the TGA of crystalline pyronaridine-Form I.

FIG. 30 depicts the characteristic X-ray diffraction pattern of thecrystalline pyronaridine-Form II.

FIG. 31A depicts the DSC of crystalline pyronaridine-Form II.

FIG. 31B depicts the TGA of crystalline pyronaridine-Form II.

FIG. 32 depicts the characteristic X-ray diffraction pattern of thecrystalline pyronaridine-Form III.

FIG. 33A depicts the DSC of crystalline pyronaridine-Form III.

FIG. 33B depicts the TGA of crystalline pyronaridine-Form III.

FIG. 34 depicts the characteristic X-ray diffraction pattern of thecrystalline pyronaridine-Form IV.

FIG. 35A depicts the DSC of crystalline pyronaridine-Form IV.

FIG. 35B depicts the TGA of crystalline pyronaridine-Form IV.

FIG. 36 depicts the characteristic X-ray diffraction pattern of thecrystalline pyronaridine-Form V.

FIG. 37 depicts the DSC of crystalline pyronaridine-Form V.

FIG. 38 depicts the rat exposure of Atovaquone following IMadministration of Compound 33 in sesame oil.

FIG. 39 depicts the rat exposure of ELQ-300 following IM administrationof Compound 35.

FIG. 40 depicts the exposure of ELQ-300 following IM administration ofCompound 2 (8 and 24 mg/kg).

FIG. 41 depicts the characteristic X-ray diffraction pattern ofcrystalline Compound 2.

FIG. 42A depicts the DSC of crystalline Compound 2.

FIG. 42B depicts the TGA of crystalline Compound 2.

DETAILED DESCRIPTION OF THE INVENTION

Seasonal malaria chemoprevention (SMC) has been an effective strategy toreduce malaria mortality and morbidity rates by up to 75% in childrenaged 3-59 months. Provided as recurring monthly doses given throughoutthe season of highest malaria transmission (3-4 months), a single oralor injectable dose would be preferred to ensure continuous coveragethroughout the entire season and simplify patient compliance to maximizechemoprevention with a target efficacy goal of ≥95%. Although manytreatments are under development, the challenge of producing a widelyavailable single-dose treatment that provides a high level of protectionfor a sustained period is still to be met.

Disclosed herein are new formulations comprising derivatives ofatovaquone, an approved antimalarial compound or comprising derivativesof ELQ-300. New sustained release formulations, such as depotformulation, comprising these derivatives are investigated. Disclosedherein are new suspension formulations comprising nanoparticles ormicroparticles of new crystalline forms of ELQ-300, atovaquone, orpyronaridine. Also disclosed herein are new suspension formulationscomprising nanoparticles or microparticles of crystalline derivatives ofatovaquone or comprising crystalline derivatives of a ELQ-300. Disclosedherein are method of treating or preventing malaria comprisingadministering one of these new formulations to a subject in needthereof.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a linear or branched hydrocarbon chain radical, whichis fully saturated, has from one to thirty carbon atoms, and is attachedto the rest of the molecule by a single bond. Alkyls comprising anynumber of carbon atoms from 1 to 30 are included. An alkyl comprising upto 30 carbon atoms is referred to as a C₁-C₃₀ alkyl, likewise, forexample, an alkyl comprising up to 12 carbon atoms is a C₁-C₁₂ alkyl.Alkyls (and other moieties defined herein) comprising other numbers ofcarbon atoms are represented similarly. Alkyl groups include, but arenot limited to, C₁-C₃₀ alkyl, C₁-C₂₀ alkyl, C₁-C₁₅ alkyl, C₁-C₁₀ alkyl,C₁-C₈ alkyl, C₁-C₆ alkyl, C₁-C₄ alkyl, C₁-C₃ alkyl, C₁-C₂ alkyl, C₂-C₈alkyl, C₃-C₈ alkyl, C₄-C₅ alkyl, C₅-C₁₂ alkyl, and C₇-C₂₀ alkyl.Representative alkyl groups include, but are not limited to, methyl,ethyl, propyl, butyl, butyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decanyl, undecanyl, dodecane, tridecane, tetradecane, pentadecane,hexadecane, heptadecane, octadecane, nonadecane, icosane, and the like.Representative alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, i-butyl, s-butyl,n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. Representativelinear alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, n-butyl, n-pentyl and the like. The alkyl may be

wherein each p and q is independently 0-18. Unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)OR^(a) (where t is 1 or2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂ (where tis 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each R^(f) is independently alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl. An alkyl may be optionally substitutedwith one or more of oxo, halogen, —OR^(a), —CN, and —N(R^(a))₂. An alkylmay be optionally substituted with one or more of oxo, halogen, —OH,—CN, and —NH₂.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twentycarbon atoms. An alkenyl comprising up to 30 carbon atoms is referred toas a C₂-C₃₀ alkenyl, likewise, for example, an alkenyl comprising up to12 carbon atoms is a C₂-C₁₂ alkenyl. Alkenyls (and other moietiesdefined herein) comprising other numbers of carbon atoms are representedsimilarly. Alkenyl groups include, but are not limited to C₂-C₃₀alkenyl, C₂-C₂₀ alkenyl, C₂-C₁₅ alkenyl, C₂-C₁₀ alkenyl, C₂-C₈ alkenyl,C₂-C₆ alkenyl, C₂-C₄ alkenyl, C₂-C₃ alkenyl, C₂-C₈ alkenyl, C₃-C₈alkenyl, C₄-C₈ alkenyl, C₅-C₁₂ alkenyl, and C₇-C₂₀ alkenyl. The alkenylis attached to the rest of the molecule by a single bond, for example,ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. The alkenyl may be

wherein each n and m is independently 0-18. Unless stated otherwisespecifically in the specification, an alkenyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each R^(f) is independently alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl. An alkenyl may be optionally substitutedwith one or more of oxo, halogen, —OR^(a), —CN, and —N(R^(a))₂. Analkenyl may be optionally substituted with one or more of oxo, halogen,—OH, —CN, and —NH₂.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twenty carbonatoms. An alkynyl comprising up to 30 carbon atoms is referred to as aC₂-C₃₀ alkynyl, likewise, for example, an alkynyl comprising up to 12carbon atoms is a C₂-C₁₂ alkynyl. Alkynyls (and other moieties definedherein) comprising other numbers of carbon atoms are representedsimilarly. Alkynyl groups include, but are not limited to C₂-C₃₀alkynyl, C₂-C₂₀ alkynyl, C₂-C₁₅ alkynyl, C₂-C₁₀ alkynyl, C₂-C₈ alkynyl,C₂-C₆ alkynyl, C₂-C₄ alkynyl, C₂-C₃ alkynyl, C₂-C₈ alkynyl, C₃-C₈alkynyl, C₄-C₅ alkynyl, C₅-C₁₂ alkynyl, and C₇-C₂₀ alkynyl. The alkynylis attached to the rest of the molecule by a single bond, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unlessstated otherwise specifically in the specification, an alkynyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f),—N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each R^(f) is independently alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. An alkynyl may beoptionally substituted with one or more of oxo, halogen, —OR^(a), —CN,and —N(R^(a))₂. An alkynyl may be optionally substituted with one ormore of oxo, halogen, —OH, —CN, and —NH₂.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group arethrough one carbon in the alkylene chain or through any two carbonswithin the chain. An alkylene may comprise one to eight carbon atoms(e.g., C₁-C₈ alkylene). An alkylene may comprise one to five carbonatoms (e.g., C₁-C₅ alkylene). An alkylene may comprise one to fourcarbon atoms (e.g., C₁-C₄ alkylene). An alkylene may comprise one tothree carbon atoms (e.g., C₁-C₃ alkylene). An alkylene may comprise oneto two carbon atoms (e.g., C₁-C₂ alkylene). An alkylene may comprise onecarbon atom (e.g., C₁ alkylene). An alkylene may comprise five to eightcarbon atoms (e.g., C₅-C₈ alkylene An alkylene may comprise two to fivecarbon atoms (e.g., C₂-C₅ alkylene An alkylene may comprise three tofive carbon atoms (e.g., C₃-C₅ alkylene). Unless stated otherwisespecifically in the specification, an alkylene chain is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each R^(f) is independently alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl. An alkylene may be optionally substitutedwith one or more of oxo, halogen, —OR^(a), —CN, and —N(R^(a))₂. Analkylene may be optionally substituted with one or more of oxo, halogen,—OH, —CN, and —NH₂.

“Aminoalkyl” refers to a radical of the formula —R^(c)—N(R^(a))₂ or—R^(c)—N(R^(a))—R^(c), where each R^(c) is independently an alkylenechain as defined above, for example, methylene, ethylene, and the like;and each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical of the formula —OR^(a) where R^(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed above for alkyl.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused (when fused with acycloalkyl or heterocycloalkyl ring, the aryl is bonded through anaromatic ring atom) or bridged ring systems. Aryl radicals include, butare not limited to, aryl radicals derived from the hydrocarbon ringsystems of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene,s-indacene, indane, indene, naphthalene, phenalene, phenanthrene,pleiadene, pyrene, and triphenylene. Unless stated otherwisespecifically in the specification, an aryl group is optionallysubstituted by one or more of the following substituents: alkyl,alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl,aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocycloalkyl (optionally substituted with one or more alkyl groups),heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, or two R^(a)attached to the same nitrogen atom are combined to form aheterocycloalkyl, each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated. An arylmay be optionally substituted with one or more of halogen, alkyl,—OR^(a), —CN, and —N(R^(a))₂. An aryl may be optionally substituted withone or more of halogen, methyl, —OH, —CN, and —NH₂.

“Aryloxy” refers to a radical bonded through an oxygen atom of theformula —O-aryl, where aryl is as defined above.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Cycloalkyl” or “carbocycle” refers to a stable, non-aromatic,monocyclic or polycyclic carbocyclic ring, which may include fused (whenfused with an aryl or a heteroaryl ring, the cycloalkyl is bondedthrough a non-aromatic ring atom) or bridged ring systems, which issaturated or unsaturated comprising 2 to 20 carbon atoms. Cycloalkylsinclude, but are not limited to C₃-C₂₀ cycloalkyl, C₃-C₁₅ cycloalkyl,C₃-C₁₀ cycloalkyl, C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, C₃-C₅ cycloalkyl,and C₃-C₄ cycloalkyl, C₂-C₈ cycloalkyl, C₃-C₈ cycloalkyl, C₄-C₈cycloalkyl, C₅-C₁₂ cycloalkyl, and C₇-C₂₀ cycloalkyl. Monocycliccycloalkyls or carbocycles include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.Polycyclic cycloalkyls or carbocycles include, for example, adamantyl,norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane,cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane,and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise statedspecifically in the specification, the cycloalkyl is optionallysubstituted by one or more substituents independently selected fromalkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated. A cycloalkyl may be optionallysubstituted with one or more of oxo, halogen, alkyl, —OR^(a), —CN, and—N(R^(a))₂. A cycloalkyl may be optionally substituted with one or moreof oxo, halogen, methyl, —OH, —CN, and —NH₂.

“Cycloalkylalkyl” refers to a radical of the formula —R^(c)-cycloalkylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the cycloalkyl radical are optionally substituted as defined above.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure. When the fused ring is a heretocycloalkylring or a heteroaryl ring, any carbon atom on the existing ringstructure which becomes part of the fused heretocycloalkyl ring or thefused heteroaryl ring may be replaced with a nitrogen atom.

“Heteroalkyl” refers to a straight or branched hydrocarbon chain alkylradical containing no unsaturation, having from one to fifteen carbonatoms (e.g., C₁-C₁₅ alkyl) consisting of carbon and hydrogen atoms andone or two heteroatoms selected from O, N, and S, wherein the nitrogenor sulfur atoms may be optionally oxidized and the nitrogen atom may bequaternized. The heteroatom(s) may be placed at any position of theheteroalkyl group including between the rest of the heteroalkyl groupand the fragment to which it is attached. The heteroalkyl is attached tothe rest of the molecule by a single bond. Unless stated otherwisespecifically in the specification, a heteroalkyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each R^(f) is independently alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. Halogen mayrefer to chloro or fluoro. Halogen may refer to fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

“Haloalkoxy” similarly refers to a radical of the formula —ORa where Rais a haloalkyl radical as defined. Unless stated otherwise specificallyin the specification, a haloalkoxy group may be optionally substitutedas described below.

“Heterocycloalkyl” or “heterocycle” refers to a stable 3- to 24-memberednon-aromatic ring radical comprising 2 to 23 carbon atoms and from oneto 8 heteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur. Heterocycloalkyls include, but are not limitedto C₂-C₂₀ heterocycloalkyl, C₂-C₁₅ heterocycloalkyl, C₂-C₁₀heterocycloalkyl, C₂-C₈ heterocycloalkyl, C₂-C₆ heterocycloalkyl, C₂-C₅heterocycloalkyl, and C₂-C₄ heterocycloalkyl, C₂-C₈ heterocycloalkyl,C₃-C₈ heterocycloalkyl, C₄-C₈ heterocycloalkyl, C₅-C₁₂ heterocycloalkyl,and C₇-C₂° heterocycloalkyl. Unless stated otherwise specifically in thespecification, the heterocycloalkyl radical may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fused(when fused with an aryl or a heteroaryl ring, the heterocycloalkyl isbonded through a non-aromatic ring atom) or bridged ring systems; andthe nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical maybe optionally oxidized; the nitrogen atom may be optionally quaternized;and the heterocycloalkyl radical may be partially or fully saturated.Examples of such heterocycloalkyl radicals include, but are not limitedto, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl,methyl-2-oxo-1,3-dioxol-4-yl, 2-oxo-1,3-dioxol-4-yl,1,1-dioxidotetrahydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl, andtetrahydro-2H-pyranyl. The term heterocycloalkyl also includes all ringforms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides and the oligosaccharides. Unlessotherwise noted, heterocycloalkyls have from 2 to 10 carbons in thering. It is understood that when referring to the number of carbon atomsin a heterocycloalkyl, the number of carbon atoms in theheterocycloalkyl is not the same as the total number of atoms (includingthe heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atomsof the heterocycloalkyl ring). Unless stated otherwise specifically inthe specification, a heterocycloalkyl group is optionally substituted byone or more of the following substituents selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated. A heterocycloalkyl may beoptionally substituted with one or more of oxo, halogen, alkyl, —OR^(a),—CN, and —N(R^(a))₂. A heterocycloalkyl may be optionally substitutedwith one or more of oxo, halogen, methyl, —OH, —CN, and —NH₂.

“Heterocycloalkyllalkyl” refers to a radical of the formula—R^(c)-heterocycloalkyl where R^(c) is an alkylene chain as definedabove. If the heterocycloalkyl is a nitrogen-containingheterocycloalkyl, the heterocycloalkyl is optionally attached to thealkyl radical at the nitrogen atom. The alkylene chain of theheterocycloalkylslkyl radical is optionally substituted as defined abovefor an alkylene chain. The heterocycloalkyl part of theheterocycloalkylalkyl radical is optionally substituted as defined abovefor a heterocycloalkyl group.

“Heterocycloalkylalkoxy” refers to a radical bonded through an oxygenatom of the formula —O—R^(c)-heterocycloalkyl where R^(c) is an alkylenechain as defined above. If the heterocycloalkyl is a nitrogen-containingheterocycloalkyl, the heterocycloalkyl is optionally attached to thealkyl radical at the nitrogen atom. The alkylene chain of theheterocycloalkylalkoxy radical is optionally substituted as definedabove for an alkylene chain. The heterocycloalkyl part of theheterocycloalkylalkoxy radical is optionally substituted as definedabove for a heterocycloalkyl group.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. The heteroarylmay be is a 5-membered heteroaryl. The heteroaryl may be a 6-memberedheteroaryl. For purposes of this invention, the heteroaryl radical maybe a monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichmay include fused (when fused with a cycloalkyl or heterocycloalkylring, the heteroaryl is bonded through an aromatic ring atom) or bridgedring systems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group is optionallysubstituted by one or more of the following substituents selected fromalkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl,optionally substituted heterocycloalkylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated. A heteroarylmay be optionally substituted with one or more of halogen, alkyl,—OR^(a), —CN, and —N(R^(a))₂. A heteroaryl may be optionally substitutedwith one or more of halogen, methyl, —OH, —CN, and —NH₂.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroaryloxy” refers to radical bonded through an oxygen atom of theformula —O-heteroaryl, where heteroaryl is as defined above.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may exist as tautomers. In circumstanceswhere tautomerization is possible, a chemical equilibrium of thetautomers will exist. The exact ratio of the tautomers depends onseveral factors, including physical state, temperature, solvent, and pH.Some examples of tautomeric equilibrium include:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. “Optionally substituted” and “substituted orunsubstituted” and “unsubstituted or substituted” are usedinterchangeably herein.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the compoundsdescribed herein is intended to encompass any and all pharmaceuticallysuitable salt forms. Preferred pharmaceutically acceptable salts of thecompounds described herein are pharmaceutically acceptable acid additionsalts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fiumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. The pharmaceutically acceptable base addition salts maybe formed with metals or amines, such as alkali and alkaline earthmetals or organic amines. Salts derived from inorganic bases include,but are not limited to, sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, for example, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline,betaine, ethylenediamine, ethylenedianiline, N-methylglucamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. See Bergeet al., supra.

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The term “about” when referring to a number or a numerical range meansthat the number or numerical range referred to is an approximationwithin experimental variability (or within statistical experimentalerror), and thus the number or numerical range varies between 1% and 10%of the stated number or numerical range.

The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatwhich in other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, “consist of” or “consist essentially of” the describedfeatures.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The term “nanoparticles” refers to particles in the nanometer range. Thesize of the particles should be below a maximum size above whichadministration by subcutaneous or intramuscular injection becomesimpaired or even no longer is possible. Said maximum size depends forexample on the limitations imposed by the needle diameter or by adversereactions of the body to large particles, or both.

The term “microparticles” refers to particles in the micrometer range.The size of the particles should be below a maximum size above whichadministration by subcutaneous or intramuscular injection becomesimpaired or even no longer is possible. Said maximum size depends forexample on the limitations imposed by the needle diameter or by adversereactions of the body to large particles, or both.

As used herein, “to treat” a condition or “treatment” of the condition(e.g., malaria) is an approach for obtaining beneficial or desiredresults, such as clinical results. Beneficial or desired results caninclude, but are not limited to, alleviation or amelioration of one ormore symptoms or conditions; diminishment of extent of disease,disorder, or condition; stabilized (i.e., not worsening) state ofdisease, disorder, or condition; preventing spread of disease, disorder,or condition (e.g., preventing the spread of Plasmodium infection beyondthe liver, preventing systemic disease, preventing the symptomatic stageof malaria, and/or preventing establishment of Plasmodium infection);delay or slowing the progress of the disease, disorder, or condition;amelioration or palliation of the disease, disorder, or condition; andremission (whether partial or total), whether detectable orundetectable. “Palliating” a disease, disorder, or condition means thatthe extent and/or undesirable clinical manifestations of the disease,disorder, or condition are lessened and/or time course of theprogression is slowed or lengthened, as compared to the extent or timecourse in the absence of treatment.

As used herein, “preventing” includes preventing the initiation ofmalaria and/or reducing the severity or intensity of malaria.

Compounds

Described herein are compounds of Formula (I′) or a pharmaceuticallyacceptable salt, solvate, polymorphs, or stereoisomer thereof:

wherein:

-   -   R is —CH₂OC(═O)R¹, —R², —C(═O)OR³, or —C(═O)R⁴;    -   R¹ is optionally substituted C₁-C₂₀alkyl, optionally substituted        C₂-C₂₀alkenyl, optionally substituted C₂-C₂₀alkynyl, optionally        substituted C₃-C₈cycloalkyl, or optionally substituted        C₂-C₈heterocycloalkyl;    -   R² is optionally substituted (C₁-C₆alkylene)aryl, optionally        substituted (C₁-C₆alkylene)heteroaryl, optionally substituted        (C₁-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted        (C₁-C₆alkylene)C₂-C₈heterocycloalkyl;    -   R³ is optionally substituted C₁-C₂₀alkyl, optionally substituted        C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl; provided        that R³ is not ethyl; and    -   R⁴ is optionally substituted C₁-C₂₀alkyl, optionally substituted        C₂-C₂alkenyl, or optionally substituted C₂-C₂₀alkynyl.

Described herein are compounds of Formula (I) or a pharmaceuticallyacceptable salt, solvate, polymorphs, or stereoisomer thereof:

wherein:

-   -   R is —C(R^(1a))₂OC(═O)R¹, —R², —C(═O)OR³, or —C(═O)R⁴;    -   R¹ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, optionally substituted C₂-C₃₀alkynyl, optionally        substituted C₃-C₈cycloalkyl, or optionally substituted        C₂-C₈heterocycloalkyl; each R^(1a) is independently hydrogen,        halogen, or optionally substituted C₁-C₆alkyl; or two R^(1a) are        taken together with the carbon atom to which they are attached        to form an optionally substituted C₃-C₈cycloalkyl;    -   R² is optionally substituted (C₁-C₆alkylene)aryl, optionally        substituted (C₁-C₆alkylene)heteroaryl, optionally substituted        (C₁-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted        (C₁-C₆alkylene)C₂-C₈heterocycloalkyl;    -   R³ is optionally substituted C₅-C₃₀alkyl, optionally substituted        C₄-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl; and    -   R⁴ is optionally substituted C₅-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl.

In a compound of Formula (I), R may be —C(R^(1a))₂OC(═O)R¹, —C(═O)OR³,or —C(═O)R⁴. In a compound of Formula (I), R may be —C(R^(1a))₂OC(═O)R¹or —C(═O)OR³. In a compound of Formula (I), R may be —C(R^(1a))₂OC(═O)R¹or —C(═O)R⁴. In a compound of Formula (I), R may be —C(═O)OR³ or—C(═O)R⁴.

In a compound of Formula (I), R may be —C(R^(1a))₂OC(═O)R¹. In acompound of Formula (I), R may be —C(R^(1a))₂OC(═O)R¹ and R^(1a) mayeach be hydrogen. In a compound of Formula (I), R may be—C(R^(1a))₂OC(═O)R¹ and R^(1a) may each be C₁-C₆alkyl. In a compound ofFormula (I), R may be —C(R^(1a))₂OC(═O)R¹ and one R^(1a) may beC₁-C₆alkyl and one R^(1a) may be hydrogen. In a compound of Formula (I),R may be —C(R^(1a))₂OC(═O)R¹ and one R^(1a) may be halogen and oneR^(1a) may be hydrogen. In a compound of Formula (I), R may be—CH₂OC(═O)R¹. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹may be optionally substituted C₁-C₂₀alkyl, optionally substitutedC₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl. In a compound ofFormula (I), R may be —CH₂OC(═O)R¹ and R¹ may be optionally substitutedC₁-C₂₀alkyl or optionally substituted C₂-C₂₀alkenyl. In a compound ofFormula (I), R may be —CH₂OC(═O)R¹ and R¹ may be optionally substitutedC₁-C₂₀alkyl or optionally substituted C₂-C₃₀alkenyl. In a compound ofFormula (I), R may be —CH₂OC(═O)R¹ and R¹ may be C₁-C₂₀alkyl orC₂-C₂₀alkenyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ andR¹ may be C₁-C₂₀alkyl or C₂-C₃₀alkenyl. In a compound of Formula (I), Rmay be —CH₂OC(═O)R¹ and R¹ may be C₁-C₃₀alkyl. In a compound of Formula(I), R may be —CH₂OC(═O)R¹ and R¹ may be C₁-C₂₅alkyl. In a compound ofFormula (I), R may be —CH₂OC(═O)R¹ and R¹ may be C₁-C₂₀alkyl. In acompound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹ may beC₁-C₁₅alkyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹may be C₁-C₆alkyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹and R¹ may be C₁-C₇alkyl. In a compound of Formula (I), R may be—CH₂OC(═O)R¹ and R¹ may be C₇-C₂₀alkyl. In a compound of Formula (I), Rmay be —CH₂OC(═O)R¹ and R¹ may be substituted C₁-C₂₀alkyl or substitutedC₂-C₂₀alkenyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ andR¹ may be substituted C₁-C₂₀alkyl or substituted C₂-C₃₀alkenyl. In acompound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹ may be substitutedC₁-C₃₀alkyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹may be substituted C₁-C₂₅alkyl. In a compound of Formula (I), R may be—CH₂OC(═O)R¹ and R¹ may be substituted C₁-C₂₀alkyl. In a compound ofFormula (I), R may be —CH₂OC(═O)R¹ and R¹ may be substitutedC₁-C₁₅alkyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹may be substituted C₁-C₆alkyl. In a compound of Formula (I), R may be—CH₂OC(═O)R¹ and R¹ may be substituted C₁-C₇alkyl. In a compound ofFormula (I), R may be —CH₂OC(═O)R¹ and R¹ may be substitutedC₇-C₂₀alkyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹may be

In a compound of Formula (I), R may be CH₂OC(═O)R¹ and R¹ may be

In a compound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹ may beC₂-C₃₀alkenyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ andR¹ may be C₂-C₆alkenyl. In a compound of Formula (I), R may be—CH₂OC(═O)R¹ and R¹ may be C₇-C₃₀alkenyl. In a compound of Formula (I),R may be —CH₂OC(═O)R¹ and R¹ may be C₁₅-C₂₀alkenyl. In a compound ofFormula (I), R may be —CH₂OC(═O)R¹ and R¹ may be C₁₅-C₃₀alkenyl. In acompound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹ may beC₂₀-C₃₀alkenyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ andR¹ may be substituted C₂-C₃₀alkenyl. In a compound of Formula (I), R maybe —CH₂OC(═O)R¹ and R¹ may be substituted C₂-C₆alkenyl. In a compound ofFormula (I), R may be —CH₂OC(═O)R¹ and R¹ may be substitutedC₇-C₃₀alkenyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ andR¹ may be substituted C₁₅-C₂₀alkenyl. In a compound of Formula (I), Rmay be —CH₂OC(═O)R¹ and R¹ may be substituted C₁₅-C₃₀alkenyl. In acompound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹ may be substitutedC₂₀-C₃₀alkenyl. In a compound of Formula (I), R may be —CH₂OC(═O)R¹ andR¹ may be

wherein R⁵ is H or methyl; n is 0-18; and m is 0-18; provided that n+mis less than 18 when R⁵ is H or n+m is less than 17 when R⁵ is methyl.In a compound of Formula (I), n may be 0. In a compound of Formula (I),n may be 1. In a compound of Formula (I), n may be 2. In a compound ofFormula (I), n may be 3. In a compound of Formula (I), n may be 4. In acompound of Formula (I), n may be 5. In a compound of Formula (I), n maybe 6. In a compound of Formula (I), n may be 7. In a compound of Formula(I), n may be 8. In a compound of Formula (I), n may be 9. In a compoundof Formula (I), n may be 10. In a compound of Formula (I), n may be 11.In a compound of Formula (I), n may be 12. In a compound of Formula (I),n may be 13. In a compound of Formula (I), n may be 14. In a compound ofFormula (I), n may be 15. In a compound of Formula (I), n may be 16. Ina compound of Formula (I), n may be 17. In a compound of Formula (I), nmay be 18. In a compound of Formula (I), m may be 0. In a compound ofFormula (I), m may be 1. In a compound of Formula (I), m may be 2. In acompound of Formula (I), m may be 3. In a compound of Formula (I), m maybe 4. In a compound of Formula (I), m may be 5. In a compound of Formula(I), m may be 6. In a compound of Formula (I), m may be 7. In a compoundof Formula (I), m may be 8. In a compound of Formula (I), m may be 9. Ina compound of Formula (I), m may be 10. In a compound of Formula (I), mmay be 11. In a compound of Formula (I), m may be 12. In a compound ofFormula (I), m may be 13. In a compound of Formula (I), m may be 14. Ina compound of Formula (I), m may be 15. In a compound of Formula (I), mmay be 16. In a compound of Formula (I), m may be 17. In a compound ofFormula (I), m may be 18.

In a compound of Formula (I), R may be —CH₂OC(═O)R¹ and R¹ may be

In a compound of Formula (I), R may be —C(═O)OR³. In a compound ofFormula (I), R may be —C(═O)OR³ and R³ may be optionally substitutedC₅-C₂₀alkyl, optionally substituted C₄-C₂₀alkenyl, or optionallysubstituted C₂-C₂₀alkynyl. In a compound of Formula (I), R may be—C(═O)OR³ and R³ may be optionally substituted C₂-C₂₀alkyl or optionallysubstituted C₄-C₂₀alkenyl. In a compound of Formula (I), R may be—C(═O)OR³ and R³ may be C₅-C₃₀alkyl. In a compound of Formula (I), R maybe —C(═O)OR³ and R³ may be C₅-C₂₀alkyl. In a compound of Formula (I), Rmay be —C(═O)OR³ and R³ may be C₅-C₁₀alkyl. In a compound of Formula(I), R may be —C(═O)OR³ and R³ may be C₁₁-C₃₀alkyl. In a compound ofFormula (I), R may be —C(═O)OR³ and R³ may be C₅-C₁₅alkyl. In a compoundof Formula (I), R may be —C(═O)OR³ and R³ may be C₆-C₁₆alkyl. In acompound of Formula (I), R may be —C(═O)OR³ and R³ may be substitutedC₅-C₃₀alkyl. In a compound of Formula (I), R may be —C(═O)OR³ and R³ maybe substituted C₅-C₂₀alkyl. In a compound of Formula (I), R may be—C(═O)OR³ and R³ may be substituted C₅-C₁₀alkyl. In a compound ofFormula (I), R may be —C(═O)OR³ and R³ may be substituted C₁₁-C₃₀alkyl.In a compound of Formula (I), R may be —C(═O)OR³ and R³ may besubstituted C₅-C₁₅alkyl. In a compound of Formula (I), R may be—C(═O)OR³ and R³ may be substituted C₆-C₁₆alkyl. In a compound ofFormula (I), R may be —C(═O)OR³ and R³ may be

wherein R⁶ is H or methyl; p is 0 to 18; and q is 0 to 18; provided thatp+q is less than 18 when R⁶ is H or p+q is less than 17 when R⁶ ismethyl; and provided that R³ is not ethyl. In a compound of Formula (I),p may be 0. In a compound of Formula (I), p may be 1. In a compound ofFormula (I), p may be 2. In a compound of Formula (I), p may be 3. In acompound of Formula (I), p may be 4. In a compound of Formula (I), p maybe 5. In a compound of Formula (I), p may be 6. In a compound of Formula(I), p may be 7. In a compound of Formula (I), p may be 8. In a compoundof Formula (I), p may be 9. In a compound of Formula (I), p may be 10.In a compound of Formula (I), p may be 11. In a compound of Formula (I),p may be 12. In a compound of Formula (I), p may be 13. In a compound ofFormula (I), p may be 14. In a compound of Formula (I), p may be 15. Ina compound of Formula (I), p may be 16. In a compound of Formula (I), pmay be 17. In a compound of Formula (I), p may be 18. In a compound ofFormula (I), q may be 0. In a compound of Formula (I), q may be 1. In acompound of Formula (I), q may be 2. In a compound of Formula (I), q maybe 3. In a compound of Formula (I), q may be 4. In a compound of Formula(I), q may be 5. In a compound of Formula (I), q may be 6. In a compoundof Formula (I), q may be 7. In a compound of Formula (I), q may be 8. Ina compound of Formula (I), q may be 9. In a compound of Formula (I), qmay be 10. In a compound of Formula (I), q may be 11. In a compound ofFormula (I), q may be 12. In a compound of Formula (I), q may be 13. Ina compound of Formula (I), q may be 14. In a compound of Formula (I), qmay be 15. In a compound of Formula (I), q may be 16. In a compound ofFormula (I), q may be 17. In a compound of Formula (I), q may be 18. Ina compound of Formula (I), R may be —C(═O)OR³ and R³ may be

In a compound of Formula (I), R may be C(═O)R⁴.

In a compound of Formula (I), R may be —C(═O)R⁴ and R⁴ may beC₅-C₃₀alkyl. In a compound of Formula (I), R may be —C(═O)R⁴ and R⁴ maybe optionally substituted C₅-C₂₀alkyl, optionally substitutedC₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl. In a compound ofFormula (I), R may be —C(═O)R⁴ and R⁴ may be optionally substitutedC₅-C₂₀alkyl or optionally substituted C₂-C₂₀alkenyl. In a compound ofFormula (I), R may be —C(═O)R⁴ and R⁴ may be C₅-C₃₀alkyl. In a compoundof Formula (I), R may be —C(═O)R⁴ and R⁴ may be C₅-C₂₀alkyl. In acompound of Formula (I), R may be —C(═O)R⁴ and R⁴ may be C₅-C₁₀alkyl. Ina compound of Formula (I), R may be C(═O)R⁴ and R⁴ may be C₁₁-C₃₀alkyl.In a compound of Formula (I), R may be —C(═O)R⁴ and R⁴ may beC₅-C₁₅alkyl. In a compound of Formula (I), R may be —C(═O)R⁴ and R⁴ maybe C₁₅-C₃₀alkyl. In a compound of Formula (I), R may be —C(═O)R⁴ and R⁴may be C₁₅-C₂₅alkyl. In a compound of Formula (I), R may be —C(═O)R⁴ andR⁴ may be substituted C₅-C₃₀alkyl. In a compound of Formula (I), R maybe —C(═O)R⁴ and R⁴ may be substituted C₅-C₂₀alkyl. In a compound ofFormula (I), R may be —C(═O)R⁴ and R⁴ may be substituted C₅-C₁₀alkyl. Ina compound of Formula (I), R may be —C(═O)R⁴ and R⁴ may be substitutedC₁₁-C₃₀alkyl. In a compound of Formula (I), R may be —C(═O)R⁴ and R⁴ maybe substituted C₅-C₁₅alkyl. In a compound of Formula (I), R may be—C(═O)R⁴ and R⁴ may be substituted C₁₅-C₃₀alkyl. In a compound ofFormula (I), R may be —C(═O)R⁴ and R⁴ may be substituted C₁₅-C₂₅alkyl.

Described herein are compounds of Formula (II′) or a pharmaceuticallyacceptable salt, solvate, polymorphs, or stereoisomer thereof:

wherein:

-   -   R′ is —CH₂OC(═O)R⁷, —R⁸, —C(═O)OR⁹, or —C(═O)R¹⁰;    -   R⁷ is optionally substituted C₁-C₂₀alkyl, optionally substituted        C₂-C₂₀alkenyl, optionally substituted C₂-C₂₀alkynyl, optionally        substituted C₃-C₅cycloalkyl, or optionally substituted        C₂-C₈heterocycloalkyl;    -   R⁸ is optionally substituted (C₁-C₆alkylene)aryl, optionally        substituted (C₁-C₆alkylene)heteroaryl, optionally substituted        (C₁-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted        (C₁-C₆alkylene)C₂-C₈heterocycloalkyl;    -   R⁹ is optionally substituted C₁-C₂₀alkyl, optionally substituted        C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl; and    -   R¹⁰ is optionally substituted C₁-C₂₀alkyl, optionally        substituted C₂-C₂₀alkenyl, or optionally substituted        C₂-C₂₀alkynyl.

Described herein are compounds of Formula (II) or a pharmaceuticallyacceptable salt, solvate, polymorphs, or stereoisomer thereof:

wherein:

-   -   R′ is —C(R^(7a))₂OC(═O)R⁷, —R⁸, —C(═O)OR⁹, or —C(═O)R¹⁰;    -   R⁷ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, optionally substituted C₂-C₃₀alkynyl, optionally        substituted C₃-C₈cycloalkyl, or optionally substituted        C₂-C₈heterocycloalkyl;    -   each R^(7a) is independently hydrogen, halogen, or optionally        substituted C₁-C₆alkyl;    -   or two R^(7a) are taken together with the carbon atom to which        they are attached to form an optionally substituted        C₃-C₈cycloalkyl;    -   R⁸ is optionally substituted (C₁-C₆alkylene)aryl, optionally        substituted (C₁-C₆alkylene)heteroaryl, optionally substituted        (C₁-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted        (C₁-C₆alkylene)C₂-C₈heterocycloalkyl;    -   R⁹ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl; and    -   R¹⁰ is optionally substituted C₁-C₃₀alkyl, optionally        substituted C₂-C₃₀alkenyl, or optionally substituted        C₂-C₃₀alkynyl.

In a compound of Formula (II), R′ may be —C(R^(7a))₂OC(═O)R⁷, —C(═O)OR⁹,or —C(═O)R¹⁰. In a compound of Formula (I), R′ may be—C(R^(7a))₂OC(═O)R⁷ or —C(═O)OR⁹. In a compound of Formula (II), R′ maybe —C(R^(7a))₂OC(═O)R⁷ or —C(═O)R¹⁰. In a compound of Formula (II), R′may be —C(═O)OR⁹ or —C(═O)R¹⁰.

In a compound of Formula (II), R′ may be —C(R^(7a))₂OC(═O)R⁷. In acompound of Formula (II), R′ may be —C(R^(7a))₂OC(═O)R⁷ and R^(7a) mayeach be hydrogen. In a compound of Formula (II), R′ may be—C(R^(7a))₂OC(═O)R⁷ and R^(7a) may each be C₁-C₆alkyl. In a compound ofFormula (II), R′ may be —C(R^(7a))₂OC(═O)R⁷ and one R^(7a) may beC₁-C₆alkyl and one R^(7a) may be hydrogen. In a compound of Formula(II), R′ may be —C(R^(7a))₂OC(═O)R⁷ and one R^(7a) may be halogen andone R^(7a) may be hydrogen. In a compound of Formula (II), R′ may be—CH₂OC(═O)R⁷. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ andR⁷ may be optionally substituted C₁-C₂₀alkyl, optionally substitutedC₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl. In a compound ofFormula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may be optionallysubstituted C₁-C₂₀alkyl or optionally substituted C₂-C₃₀alkenyl. In acompound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may beoptionally substituted C₁-C₂₀alkyl or optionally substitutedC₂-C₂₀alkenyl. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ andR⁷ may be C₁-C₂₀alkyl or C₂-C₃₀alkenyl. In a compound of Formula (II),R′ may be —CH₂OC(═O)R⁷ and R⁷ may be C₁-C₂₀alkyl or C₂-C₂₀alkenyl. In acompound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may beC₁-C₃₀alkyl. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ andR⁷ may be C₁-C₂₅alkyl. In a compound of Formula (II), R′ may be—CH₂OC(═O)R⁷ and R⁷ may be C₁-C₁₅alkyl. In a compound of Formula (II),R′ may be —CH₂OC(═O)R⁷ and R⁷ may be C₁-C₂₀alkyl. In a compound ofFormula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may be C₁-C₆alkyl. In acompound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may beC₁-C₇alkyl. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷may be C₇-C₂₀alkyl. In a compound of Formula (II), R′ may be—CH₂OC(═O)R⁷ and R⁷ may be substituted C₁-C₃₀alkyl. In a compound ofFormula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may be substitutedC₁-C₂₅alkyl. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ andR⁷ may be substituted C₁-C₂₀alkyl. In a compound of Formula (II), R′ maybe —CH₂OC(═O)R⁷ and R⁷ may be substituted C₁-C₁₅alkyl. In a compound ofFormula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may be substitutedC₁-C₆alkyl. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷may be substituted C₁-C₇alkyl. In a compound of Formula (II), R′ may be—CH₂OC(═O)R⁷ and R⁷ may be substituted C₇-C₂₀alkyl. In a compound ofFormula (II), R′ may be —CH₂C(═O)R and R⁷ may be

In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may be

In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may beC₂-C₃₀alkenyl. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ andR⁷ may be C₂-C₆alkenyl. In a compound of Formula (II), R′ may be—CH₂OC(═O)R⁷ and R⁷ may be C₇-C₃₀alkenyl. In a compound of Formula (II),R′ may be —CH₂OC(═O)R⁷ and R⁷ may be C₁₅-C₂₀alkenyl. In a compound ofFormula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may be C₁₅-C₃₀alkenyl. In acompound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may beC₂₀-C₃₀alkenyl. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷and R⁷ may be substituted C₂-C₃₀alkenyl. In a compound of Formula (II),R′ may be —CH₂OC(═O)R⁷ and R⁷ may be substituted C₂-C₆alkenyl. In acompound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may besubstituted C₇-C₃₀alkenyl. In a compound of Formula (II), R′ may be—CH₂OC(═O)R⁷ and R⁷ may be substituted C₁₅-C₂₀alkenyl. In a compound ofFormula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may be substitutedC₁₅-C₃₀alkenyl. In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷and R⁷ may be substituted C₂₀-C₃₀alkenyl. In a compound of Formula (II),R′ may be —CH₂OC(═O)R⁷ and R⁷ may be

wherein R⁵ is H or methyl; n is 0-18; and m is 0-18; provided that n+mis less than 18 when R⁵ is H or n+m is less than 17 when R⁵ is methyl.In a compound of Formula (II), n may be 0. In a compound of Formula(II), n may be 1. In a compound of Formula (II), n may be 2. In acompound of Formula (II), n may be 3. In a compound of Formula (II), nmay be 4. In a compound of Formula (II), n may be 5. In a compound ofFormula (II), n may be 6. In a compound of Formula (II), n may be 7. Ina compound of Formula (II), n may be 8. In a compound of Formula (II), nmay be 9. In a compound of Formula (II), n may be 10. In a compound ofFormula (II), n may be 11. In a compound of Formula (II), n may be 12.In a compound of Formula (II), n may be 13. In a compound of Formula(II), n may be 14. In a compound of Formula (II), n may be 15. In acompound of Formula (II), n may be 16. In a compound of Formula (II), nmay be 17. In a compound of Formula (II), n may be 18. In a compound ofFormula (II), m may be 0. In a compound of Formula (II), m may be 1. Ina compound of Formula (II), m may be 2. In a compound of Formula (II), mmay be 3. In a compound of Formula (II), m may be 4. In a compound ofFormula (II), m may be 5. In a compound of Formula (II), m may be 6. Ina compound of Formula (II), m may be 7. In a compound of Formula (II), mmay be 8. In a compound of Formula (II), m may be 9. In a compound ofFormula (II), m may be 10. In a compound of Formula (II), m may be 11.In a compound of Formula (II), m may be 12. In a compound of Formula(II), m may be 13. In a compound of Formula (II), m may be 14. In acompound of Formula (II), m may be 15. In a compound of Formula (II), mmay be 16. In a compound of Formula (II), m may be 17. In a compound ofFormula (II), m may be 18.

In a compound of Formula (II), R′ may be —CH₂OC(═O)R⁷ and R⁷ may be

In a compound of Formula (II), R′ may be —C(═O)OR⁹.

In a compound of Formula (II), R′ may be —C(═O)OR⁹ and R⁹ may beoptionally substituted C₁-C₂₀alkyl, optionally substitutedC₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl. In a compound ofFormula (II), R′ may be —C(═O)OR⁹ and R⁹ may be optionally substitutedC₁-C₂₀alkyl or optionally substituted C₂-C₂₀alkenyl. In a compound ofFormula (II), R′ may be —C(═O)OR⁹ and R⁹ may be C₅-C₃₀alkyl. In acompound of Formula (II), R′ may be —C(═O)OR⁹ and R⁹ may be C₅-C₂₀alkyl.In a compound of Formula (II), R′ may be —C(═O)OR⁹ and R⁹ may beC₅-C₁₀alkyl. In a compound of Formula (II), R′ may be —C(═O)OR⁹ and R⁹may be C₁₁-C₃₀alkyl. In a compound of Formula (II), R′ may be —C(═O)OR⁹and R⁹ may be C₅-C₁₅alkyl. In a compound of Formula (II), R′ may be—C(═O)OR⁹ and R⁹ may be C₆-C₁₆alkyl. In a compound of Formula (II), R′may be —C(═O)OR⁹ and R⁹ may be substituted C₅-C₃₀alkyl. In a compound ofFormula (II), R′ may be —C(═O)OR⁹ and R⁹ may be substituted C₅-C₂₀alkyl.In a compound of Formula (II), R′ may be —C(═O)OR⁹ and R⁹ may besubstituted C₅-C₁₀alkyl. In a compound of Formula (II), R′ may be—C(═O)OR⁹ and R⁹ may be substituted C₁₁-C₃₀alkyl. In a compound ofFormula (II), R′ may be —C(═O)OR⁹ and R⁹ may be substituted C₅-C₁₅alkyl.In a compound of Formula (II), R′ may be —C(═O)OR⁹ and R⁹ may besubstituted C₆-C₁₆alkyl. In a compound of Formula (II), R′ may be—C(═O)OR⁹ and R⁹ may be

wherein R⁶ is H or methyl; p is 0 to 18; and q is 0 to 18; provided thatp+q is less than 18 when R⁶ is H or p+q is less than 17 when R⁶ ismethyl. In a compound of Formula (II), p may be 0. In a compound ofFormula (II), p may be 1. In a compound of Formula (II), p may be 2. Ina compound of Formula (II), p may be 3. In a compound of Formula (II), pmay be 4. In a compound of Formula (II), p may be 5. In a compound ofFormula (II), p may be 6. In a compound of Formula (II), p may be 7. Ina compound of Formula (II), p may be 8. In a compound of Formula (II), pmay be 9. In a compound of Formula (II), p may be 10. In a compound ofFormula (II), p may be 11. In a compound of Formula (II), p may be 12.In a compound of Formula (II), p may be 13. In a compound of Formula(II), p may be 14. In a compound of Formula (II), p may be 15. In acompound of Formula (II), p may be 16. In a compound of Formula (II), pmay be 17. In a compound of Formula (II), p may be 18. In a compound ofFormula (II), q may be 0. In a compound of Formula (II), q may be 1. Ina compound of Formula (II), q may be 2. In a compound of Formula (II), qmay be 3. In a compound of Formula (II), q may be 4. In a compound ofFormula (II), q may be 5. In a compound of Formula (II), q may be 6. Ina compound of Formula (II), q may be 7. In a compound of Formula (II), qmay be 8. In a compound of Formula (II), q may be 9. In a compound ofFormula (II), q may be 10. In a compound of Formula (II), q may be 11.In a compound of Formula (II), q may be 12. In a compound of Formula(II), q may be 13. In a compound of Formula (II), q may be 14. In acompound of Formula (II), q may be 15. In a compound of Formula (II), qmay be 16. In a compound of Formula (II), q may be 17. In a compound ofFormula (II), q may be 18. In a compound of Formula (II), R′ may be—C(═O)OR⁹ and R⁹ may be

In a compound of Formula (II), R′ may be —C(═O)R¹⁰.

In a compound of Formula (II), R′ may be —C(═O)R¹⁰ and R¹⁰ may beoptionally substituted C₁-C₂₀alkyl, optionally substitutedC₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl. In a compound ofFormula (II), R′ may be —C(═O)R¹⁰ and R¹⁰ may be optionally substitutedC₁-C₂₀alkyl or optionally substituted C₂-C₂₀alkenyl. In a compound ofFormula (II), R′ may be —C(═O)R¹⁰ and R¹⁰ may be C₅-C₃₀alkyl. In acompound of Formula (II), R′ may be —C(═O)R¹⁰ and R¹⁰ may beC₅-C₂₀alkyl. In a compound of Formula (II), R′ may be —C(═O)R¹⁰ and R¹⁰may be C₅-C₁₀alkyl. In a compound of Formula (II), R′ may be —C(═O)R¹⁰and R¹⁰ may be C₁₁-C₃₀alkyl. In a compound of Formula (II), R′ may be—C(═O)R¹⁰ and R¹⁰ may be C₅-C₁₅alkyl. In a compound of Formula (II), R′may be —C(═O)R¹⁰ and R¹⁰ may be C₁₅-C₃₀alkyl. In a compound of Formula(II), R′ may be —C(═O)R¹⁰ and R¹⁰ may be C₁₅-C₂₅alkyl. In a compound ofFormula (II), R′ may be —C(═O)R¹⁰ and R¹⁰ may be substitutedC₅-C₃₀alkyl. In a compound of Formula (II), R′ may be —C(═O)R¹⁰ and R¹⁰may be substituted C₅-C₂₀alkyl. In a compound of Formula (II), R′ may be—C(═O)R¹⁰ and R¹⁰ may be substituted C₅-C₁₀alkyl. In a compound ofFormula (II), R′ may be —C(═O)R¹⁰ and R¹⁰ may be substitutedC₁₁-C₃₀alkyl. In a compound of Formula (II), R′ may be —C(═O)R¹⁰ and R¹⁰may be substituted C₅-C₁₅alkyl. In a compound of Formula (II), R′ may be—C(═O)R¹⁰ and R¹⁰ may be substituted C₁₅-C₃₀alkyl. In a compound ofFormula (II), R′ may be —C(═O)R¹⁰ and R¹⁰ may be substitutedC₁₅-C₂₅alkyl.

Described herein are crystalline compounds of Formula (II) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   R′ is —C(R^(7a))₂OC(═O)R⁷, —R⁸, —C(═O)OR⁹, or —C(═O)R¹⁰;    -   R⁷ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, optionally substituted C₂-C₃₀alkynyl, optionally        substituted C₃-C₈cycloalkyl, or optionally substituted        C₂-C₈heterocycloalkyl;    -   each R^(7a) is independently hydrogen, halogen, or optionally        substituted C₁-C₆alkyl;    -   or two R^(7a) are taken together with the carbon atom to which        they are attached to form an optionally substituted        C₃-C₈cycloalkyl;    -   R⁸ is optionally substituted (C₁-C₆alkylene)aryl, optionally        substituted (C₁-C₆alkylene)heteroaryl, optionally substituted        (C₁-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted        (C₁-C₆alkylene)C₂-C₈heterocycloalkyl;    -   R⁹ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl; and    -   R¹⁰ is optionally substituted C₁-C₃₀alkyl, optionally        substituted C₂-C₃₀alkenyl, or optionally substituted        C₂-C₃₀alkynyl.

The crystalline compound of Formula (II) may be crystalline((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof.

The crystalline form of((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate may have at least one of the following properties:

-   -   (a) an X-Ray powder diffraction (XRPD) pattern substantially the        same as shown in FIG. 41; or

(b) an X-ray powder diffraction (XRPD) pattern comprising characteristicpeaks at about 14.4±0.1° 2θ, about 15.1±0.1° 2θ, about 17.7±0.1° 2θ,about 18.1±0.1° 2θ, about 22.3±0.1° 2θ, and about 22.6±0.1° 2θ; or

-   -   (c) a DSC thermogram substantially the same to the one set forth        in FIG. 42A; or    -   (d) a DSC thermogram with an endotherm having a peak at about        99.5° C.

The crystalline form of((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate may have an X-ray powder diffraction (XRPD) pattern furthercomprising characteristic peaks at about 19.0°±0.1° 2θ, about 20.3°±0.1°2θ, about 21.2°±0.1° 2θ, about 26.7°±0.1° 2θ, and about 29.2°±0.1° 2θ.

Described herein are compounds of Formula (III) or a pharmaceuticallyacceptable salt, solvate, polymorphs, or stereoisomer thereof:

wherein:

R¹¹ is a lipophilic moiety.

In a compound of Formula (III), R¹¹ may be optionally substitutedC₁-C₃₀alkyl, optionally substituted C₂-C₃₀alkenyl, or optionallysubstituted C₂-C₃₀alkynyl. In a compound of Formula (III), R¹¹ may beoptionally substituted C₁-C₂₀alkyl, optionally substitutedC₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl.

In a compound of Formula (III), R¹¹ may be C₁-C₂₀alkyl. In a compound ofFormula (III), R¹¹ may be C₁-C₃₀alkyl. In a compound of Formula (III),R¹¹ may be C₁-C₆alkyl. In a compound of Formula (III), R¹¹ may beC₇-C₃₀alkyl. In a compound of Formula (III), R¹¹ may be C₇-C₂₀alkyl. Ina compound of Formula (III), R¹¹ may be substituted C₁-C₂₀alkyl. In acompound of Formula (III), R¹¹ may be substituted C₁-C₃₀alkyl. In acompound of Formula (III), R¹¹ may be substituted C₁-C₆alkyl. In acompound of Formula (III), R¹¹ may be substituted C₇-C₃₀alkyl. In acompound of Formula (III), R¹¹ may be substituted C₇-C₂₀alkyl. In acompound of Formula (III), R¹¹ may be

In a compound of Formula (III), R¹¹ may be C₂-C₃₀alkenyl. In a compoundof Formula (III), R¹¹ may be C₃-C₃₀alkenyl. In a compound of Formula(III), R¹¹ may be C₆-C₃₀alkenyl. In a compound of Formula (III), R¹¹ maybe C₆-C₂₅alkenyl. In a compound of Formula (III), R¹¹ may beC₁₅-C₂₅alkenyl. In a compound of Formula (III), R¹¹ may beC₂-C₂₅alkenyl. In a compound of Formula (III), R¹¹ may be C₂-C₂₀alkenyl.In a compound of Formula (III), R¹¹ may be C₂-C₁₅alkenyl. In a compoundof Formula (III), R¹¹ may be C₂-C₁₀alkenyl. In a compound of Formula(III), R¹¹ may be C₂-C₆alkenyl. In a compound of Formula (III), R¹¹ maybe C₆-C₃₀alkenyl. In a compound of Formula (III), R¹¹ may beC₆-C₂₅alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₂-C₃₀alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₃-C₃₀alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₆-C₃₀alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₆-C₂₅alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₁₅-C₂₅alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₂-C₂₅alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₂-C₂₀alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₂-C₁₅alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₂-C₁₀alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₂-C₆alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₆-C₃₀alkenyl. In a compound of Formula (III), R¹¹ may be substitutedC₆-C₂₅alkenyl. In a compound of Formula (III), R¹¹ may be

In a compound of Formula (III), R²¹ may comprise between 1 and 10 doublebonds. In a compound of Formula (III), R²¹ may comprise between 1 and 6double bonds. In a compound of Formula (III), R²¹ may comprise between 4and 8 double bonds. In a compound of Formula (III), R²¹ may comprisebetween 4 and 6 double bonds. In a compound of Formula (III), R²¹ maycomprise between 2 and 8 double bonds. In a compound of Formula (III),R²¹ may comprise between 2 and 6 double bonds. In a compound of Formula(III), R²¹ may comprise more than 1 double bond. In a compound ofFormula (III), R²¹ may comprise more than 2 double bonds. In a compoundof Formula (III), R²¹ may comprise more than 3 double bonds. In acompound of Formula (III), R²¹ may comprise more than 4 double bonds. Ina compound of Formula (III), R²¹ may comprise more than 5 double bonds.In a compound of Formula (III), R²¹ may comprise 1 double bond. In acompound of Formula (III), R²¹ may comprise 2 double bonds. In acompound of Formula (III), R²¹ may comprise 3 double bonds. In acompound of Formula (III), R²¹ may comprise 4 double bonds. In acompound of Formula (III), R²¹ may comprise 5 double bonds. In acompound of Formula (III), R²¹ may comprise 6 double bonds.

Described herein are compounds of Formula (IV) or a pharmaceuticallyacceptable salt, solvate, polymorphs, or stereoisomer thereof:

-   -   wherein R²¹ is optionally substituted C₃-C₃₀alkenyl or        optionally substituted C₂-C₃₀alkynyl.

In a compound of Formula (IV), R²¹ may be C₃-C₃₀alkenyl orC₂-C₃₀alkynyl. In a compound of Formula (IV), R²¹ may be C₃-C₃₀alkenyl.In a compound of Formula (IV), R²¹ may be C₆-C₃₀alkenyl. In a compoundof Formula (IV), R²¹ may be C₆-C₂₅alkenyl. In a compound of Formula(IV), R²¹ may be C₁₅-C₂₅alkenyl. In a compound of Formula (IV), R²¹ maybe substituted C₃-C₃₀alkenyl. In a compound of Formula (IV), R²¹ may besubstituted C₆-C₃₀alkenyl. In a compound of Formula (IV), R²¹ may besubstituted C₆-C₂₅alkenyl. In a compound of Formula (IV), R²¹ may besubstituted C₁₅-C₂₅alkenyl. In a compound of Formula (IV), R²¹ may be

In a compound of Formula (IV), R²¹ may comprise between 1 and 10 doublebonds. In a compound of Formula (IV), R²¹ may comprise between 1 and 6double bonds. In a compound of Formula (IV), R²¹ may comprise between 4and 8 double bonds. In a compound of Formula (IV), R²¹ may comprisebetween 4 and 6 double bonds. In a compound of Formula (IV), R²¹ maycomprise between 2 and 8 double bonds. In a compound of Formula (IV),R²¹ may comprise between 2 and 6 double bonds. In a compound of Formula(IV), R²¹ may comprise more than 1 double bond. In a compound of Formula(IV), R²¹ may comprise more than 2 double bonds. In a compound ofFormula (IV), R²¹ may comprise more than 3 double bonds. In a compoundof Formula (IV), R²¹ may comprise more than 4 double bonds. In acompound of Formula (IV), R²¹ may comprise more than 5 double bonds. Ina compound of Formula (IV), R²¹ may comprise 1 double bond. In acompound of Formula (IV), R²¹ may comprise 2 double bonds. In a compoundof Formula (IV), R²¹ may comprise 3 double bonds. In a compound ofFormula (IV), R²¹ may comprise 4 double bonds. In a compound of Formula(IV), R²¹ may comprise 5 double bonds. In a compound of Formula (IV),R²¹ may comprise 6 double bonds.

Described herein are crystalline compounds of Formula (III) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

R¹¹ is a lipophilic moiety.

Described herein are crystalline forms of ELQ-300 or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

ELQ-300(6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one).The crystalline form of ELQ-300, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof may be ELQ-300-Form IA. The crystallineform of ELQ-300, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof may be ELQ-300-Form IB. The crystalline form ofELQ-300, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof may be ELQ-300-Form II. The crystalline form of ELQ-300, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof maybe ELQ-300-Form III. The crystalline form of ELQ-300, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof maybe ELQ-300-Form IV. The crystalline form of ELQ-300, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof maybe ELQ-300-Form V.

Described herein are crystalline forms of atovaquone or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

atovaquone(trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione).

The crystalline form of atovaquone, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof may be atovaquone—Form I. Thecrystalline form of atovaquone, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof may be atovaquone—Form II.

Described herein are crystalline forms of pyronaridine or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

pyronaridine(4-[(7-chloro-2-methoxy-pyrido[3,2-b]quinolin-10-yl)amino]-2,6-bis(pyrrolidin-1-ylmethyl)phenol).

The crystalline form of pyronaridine may be obtained from a pyronaridinesalt. The pyronaridine salt may be pyronaridine pamoate, pyronaridinebenzenesulfonate, pyronaridine palmitate, pyronaridine naphthalate,pyronaridine benzoate, pyronaridine edetate, pyronaridine edisylate,pyronaridine estolate, pyronaridine napsylate, pyronaridine mesylate,pyronaridine stearate, or pyronaridine valerate. The pyronaridine saltmay be pyronaridine pamoate.

The crystalline form of pyronaridine, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof may be pyronaridine-Form I. Thecrystalline form of pyronaridine, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof may be pyronaridine-Form II. Thecrystalline form of pyronaridine, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof may be pyronaridine-Form III. Thecrystalline form of pyronaridine, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof may be pyronaridine-Form V. Thecrystalline form of pyronaridine, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof may be pyronaridine-Form V.

In some embodiments, the compound disclosed herein has the structureprovided in Table 1.

TABLE 1 Comp. Name Structure  1 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl acetate

 2 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl butyrate

 3 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl isobutyrate

 4 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl hexanoate

 5 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methylcyclohexanecarboxylate

 6 4-((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl)phenylacetate

 7 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl 2-propylpentanoate

 8 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl decanoate

 9 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl tetradecanoate

10 (6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl palmitate

11 (E)-(6-chloro-7-methoxy-2-methyl-3- (4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yloxy)methyl octadec-9-enoate

12 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yl methyl carbonate

13 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yl ethyl carbonate

14 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yl propyl carbonate

15 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yl isopropyl carbonate

16 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yl hexyl carbonate

17 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yl decyl carbonate

18 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yl hexadecyl carbonate

19 6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl) quinolin-4-yl decan-2-yl carbonate

35 ((6-chloro-7-methoxy-2-methyl-3-(4- (4-(trifluoro-methoxy)phenoxy)phenyl)quinolin- 4-yl)oxy)methyl(4Z,7Z,10Z,13Z,16Z,19Z)-docosa- 4,7,10,13,16,19-hexaenoate

In some embodiments, the compound disclosed herein has the structureprovided in Table 2.

TABLE 2 Comp. Name Structure 20 3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4- dioxo-1,4-dihydronaphthalen- 2-yl acetate

21 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl propionate

22 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl butyrate

23 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl pivalate

24 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl isobutyrate

25 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl hexanoate

26 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl pentanoate

27 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl decanoate

28 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl dodecanoate

29 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl palmitate

30 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl 2-propylpentanoate

31 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl butyrate

32 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl nonanoate

33 3-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen- 2-yl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19- hexaenoate

34 2-((1r,4r)-4-(4- chlorophenyl)cyclohexyl)-3-((((4Z,7Z,10Z,13Z,16Z,19Z)- docosa-4,7,10,13,16,19- hexaen-1-yl)oxy)methoxy)naphthalene- 1,4-dione

Preparation of the Compounds

The compounds used in the reactions described herein are made accordingto known organic synthesis techniques, starting from commerciallyavailable chemicals and/or from compounds described in the chemicalliterature. “Commercially available chemicals” are obtained fromstandard commercial sources including Acros Organics (Geel, Belgium),Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka),Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville,Ill.), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada),Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.),Combi-blocks (San Diego, Calif.), Crescent Chemical Co. (Hauppauge,N.Y.), eMolecules (San Diego, Calif.), Fisher Scientific Co.(Pittsburgh, Pa.), Fisons Chemicals (Leicestershire, UK), FrontierScientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.),Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.),Matrix Scientific, (Columbia, S.C.), Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc.(Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co.(Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Ryan Scientific,Inc. (Mount Pleasant, S.C.), Spectrum Chemicals (Gardena, Calif.),Sundia Meditech, (Shanghai, China), TCI America (Portland, Oreg.), TransWorld Chemicals, Inc. (Rockville, Md.), and WuXi (Shanghai, China).

Suitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are also identified through the indicesof known chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs areoptionally prepared by custom chemical synthesis houses, where many ofthe standard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the compounds described herein is P. H. Stahl& C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag HelveticaChimica Acta, Zurich, 2002.

Further Forms of Compounds Disclosed Herein Isomers

Furthermore, the compounds described herein may exist as geometricisomers. The compounds described herein may possess one or more doublebonds. The compounds presented herein include all cis, trans, syn, anti,entgegen (E), and zusammen (Z) isomers as well as the correspondingmixtures thereof. In some situations, compounds exist as tautomers. Thecompounds described herein include all possible tautomers within theformulas described herein.

In some situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration, or Sconfiguration. The compounds described herein may possess three chiralcenters and each center exists in the R configuration, or Sconfiguration. The compounds described herein may possess four chiralcenters and each center exists in the R configuration, or Sconfiguration. The compounds described herein may include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion are useful for the applications described herein. Thecompounds described herein may be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. Dissociable complexes may be preferred (e.g.,crystalline diastereomeric salts). The diastereomers may have distinctphysical properties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. The diastereomers may be separated by chiralchromatography, or preferably, by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer may thenbe recovered, along with the resolving agent, by any practical meansthat would not result in racemization.

Labeled Compounds

The compounds described herein may exist in their isotopically-labeledforms. The methods disclosed herein may include methods of treatingdiseases by administering such isotopically-labeled compounds. Themethods disclosed herein may include methods of treating diseases byadministering such isotopically-labeled compounds as pharmaceuticalcompositions. Thus, the compounds disclosed herein may includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that areincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹p, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and pharmaceuticallyacceptable salts, esters, solvate, hydrates or derivatives thereof whichcontain the aforementioned isotopes and/or other isotopes of other atomsare within the scope of this invention. Certain isotopically-labeledcompounds, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i. e., ³H and carbon-14, i. e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavy isotopes such asdeuterium, i.e., ²H, produces certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements. The isotopically labeledcompounds, pharmaceutically acceptable salt, ester, solvate, hydrate orderivative thereof may be prepared by any suitable method.

The compounds described herein may be labeled by other means, including,but not limited to, the use of chromophores or fluorescent moieties,bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

The compounds described herein may exist as their pharmaceuticallyacceptable salts. The methods disclosed herein may include methods oftreating diseases by administering such pharmaceutically acceptablesalts. The methods disclosed herein may include methods of treatingdiseases by administering such pharmaceutically acceptable salts aspharmaceutical compositions.

The compounds described herein may possess acidic or basic groups andtherefore react with any of a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.These salts may be prepared in situ during the final isolation andpurification of the compounds of the invention, or by separatelyreacting a purified compound in its free form with a suitable acid orbase, and isolating the salt thus formed.

Solvates

The compounds described herein may exist as solvates. The inventionprovides for methods of treating diseases by administering suchsolvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, may be formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of the compounds describedherein are conveniently prepared or formed during the processesdescribed herein. By way of example only, hydrates of the compoundsdescribed herein are conveniently prepared by recrystallization from anaqueous/organic solvent mixture, using organic solvents including, butnot limited to, dioxane, tetrahydrofuran or methanol. In addition, thecompounds provided herein exist in unsolvated as well as solvated forms.In general, the solvated forms are considered equivalent to theunsolvated forms for the purposes of the compounds and methods providedherein.

Polymorphs

The compounds described herein, may be in crystalline forms, also knownas polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, melting points,density, hardness, crystal shape, optical properties, stability, andsolubility. Various factors such as the recrystallization solvent, rateof crystallization, and storage temperature may cause a single crystalform to dominate.

The crystalline form may be ELQ-300-Form IA. The crystalline form may beELQ-300-Form IB. The crystalline form may be ELQ-300-Form II. Thecrystalline form may be ELQ-300-Form III. The crystalline form may beELQ-300-Form IV. The crystalline form may be ELQ-300-Form V.

The crystalline form may be a crystalline compound of Formula (II). Thecrystalline form may be crystalline6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-ylpropionate. The crystalline form may be crystalline6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-ylethyl carbonate. The crystalline form may be crystalline(6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methylbutyrate.

The crystalline form may be atovaquone-Form I. The crystalline form maybe atovaquone-Form II.

The crystalline form may be a crystalline compound of Formula (III). Thecrystalline form may be crystalline3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yldecanoate.

The crystalline form may be pyronaridine-Form I. The crystalline formmay be pyronaridine-Form II. The crystalline form may bepyronaridine-Form III. The crystalline form may be pyronaridine-Form IV.The crystalline form may be pyronaridine-Form V.

Pharmaceutical Compositions

The compounds described herein may be formulated into pharmaceuticalcompositions. Pharmaceutical compositions are formulated in aconventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, twentyfirst Ed(Lippincott Williams & Wilkins 2012); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

The compounds described herein may be administered in combination withpharmaceutically acceptable carriers, excipients or diluents, in apharmaceutical composition. Administration of the compounds andcompositions described herein can be effected by any method that enablesdelivery of the compounds to the site of action. The compounds disclosedherein, such as compounds of Formula (II) or Formula (III) may beformulated as a depot formulation for administration via intramuscularor subcutaneous injection. The compounds disclosed herein, such ascrystalline ELQ-300 (ELQ-300-Form IA, ELQ-300-Form IB, ELQ-300-Form II,ELQ-300-Form III, ELQ-300-Form IV, or ELQ-300-Form V), crystallinecompounds of Formula (II), crystalline atovaquone (atovaquone-Form I oratovaquone-Form II), crystalline compounds of Formula (III), orcrystalline pyronaridine (pyronaridine-Form I, pyronaridine-Form II,pyronaridine-Form III, pyronaridine-Form IV, or pyronaridine-Form V) maybe formulated as suspension for administration via intramuscular orsubcutaneous injection.

Depot Formulation

Depot formulations are efficient, well-tolerated, sustained or delayedrelease compositions of the active ingredient that are therapeuticallyeffective for a number of weeks, such as at least about one week, atleast about two weeks, at least about three weeks, at least about fourweeks, at least about five weeks, at least about six weeks, at leastabout seven weeks, at least about eight weeks, at least about nineweeks, at least ten about weeks, at least about eleven weeks, at leastabout twelve weeks or more. Depot formulations are efficient,well-tolerated, sustained or delayed release compositions of the activeingredient that are therapeutically effective for a number of days, suchas at least about 5 days, at least about 10 days, at least about 15days, at least about 20 days, at least about 25 days, at least about 30days, at least about 35 days, at least about 40 days, at least about 45days, at least about 50 days, at least about 55 days, at least about 60days, at least about 65 days, at least about 70 days, at least about 75days, at least about 80 days, at least about 85 days, at least about 90days, at least about 95 days, at least about 100 days, at least about105 days, at least about 110 days, at least about 115 days, at leastabout 120 days or more.

In addition to the active agent describe herein, additional ingredientsmay be used in the depot formulations of the present invention includingsurfactants, solubilizers, emulsifiers, preservatives, isotonicityagents, dispersing agents, wetting agents, fillers, solvents, buffers,stabilizers, lubricants, thickening agents, suspending agents, andcombination thereof.

The depot formulation may comprise a compound disclosed herein and asuitable hydrophobic materials. The suitable hydrophobic material may bea monoglyceride, diglyceride, or a triglyceride. The suitablehydrophobic material may be an oil. The oil may be a biocompatible oil.The oil may be mineral oil. The oil may be castor oil. The oil may bevegetable oil. The vegetable oil may be selected from corn oil, peanutoil, sesame oil, olive oil, palm oil, safflower oil, soybean oil,cottonseed oil, rapeseed oil, sunflower oil and mixtures thereof. Theoil may be sesame oil. The oil may be a semi-synthetic vegetable oilobtained by total esterification and/or hydrolysis and/or fractionationof a natural vegetable oil, for instance fatty acid triglyceridesderived from vegetable oils, such as triglycerides of caprylic, capric,linoleic or succinic acids (sold under the trade names Miglyol™ 810,812, 818, 820, 829), esters of propylene glycol and of a fatty acid,derived from vegetable oil, such as esters of propylene glycol and ofcaprylic and capric acids (sold under the trade name Miglyol™ 840), andalso mixtures thereof.

The depot formulation may comprise a compound of Formula (II), orpharmaceutically acceptable salt, solvate, or stereoisomer thereof andan oil. The concentration of the compound of Formula (II), orpharmaceutically acceptable salt, solvate, or stereoisomer thereof inthe oil may be between about 20 mg/mL and about 500 mg/mL, between about20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20mg/mL and about 100 mg/mL, or between about 50 mg/mL and about 100mg/mL. The concentration may be at least about 20 mg/mL, at least about30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at leastabout 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, atleast about 90 mg/mL, or at least about 100 mg/mL. The concentration maybe less than about 20 mg/mL, less than about 30 mg/mL, less than about40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less thanabout 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, orless than about 100 mg/mL. The concentration may be more than about 20mg/mL, more than about 30 mg/mL, more than about 40 mg/mL, more thanabout 50 mg/mL, more than about 60 mg/mL, more than about 70 mg/mL, morethan about 80 mg/mL, more than about 90 mg/mL, more than about 100mg/mL, more than about 150 mg/mL, or more than about 200 mg/mL.

The compound of Formula (II) may be released from the depot formulationat a rate providing an average plasma concentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one(ELQ-300) of at least about 1 μM over a period of about 12 weeks. Theaverage plasma concentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be at least about 900 nM, at least about 800 nM, at least about 700nM, at least about 600 nM, at least about 500 nM, at least about 400 nM,at least about 300 nM, at least about 200 nM, at least about 100 nM, atleast about 95 nM, at least about 90 nM, at least about 85 nM, at leastabout 80 nM, at least about 75 nM, at least about 70 nM, at least about65 nM, at least about 60 nM, at least about 55 nM, at least about 50 nM,at least about 45 nM, at least about 40 nM, at least about 35 nM, atleast about 30 nM, at least about 25 nM, or at least about 20 nM over aperiod of about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks,about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4weeks, about 3 weeks, about 2 weeks, or about 1 week. The average plasmaconcentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be at least about 100 nM over a period of about 4 weeks uponadministration of a compound of Formula (II).

The depot formulation may comprise a compound of Formula (III), orpharmaceutically acceptable salt, solvate, or stereoisomer thereof andan oil. The concentration of the compound of Formula (III), orpharmaceutically acceptable salt, solvate, or stereoisomer thereof inthe oil may be between about 20 mg/mL and about 500 mg/mL, between about20 mg/mL and about 400 mg/mL, between about 20 mg/mL and about 300mg/mL, between about 20 mg/mL and about 200 mg/mL, between about 20mg/mL and about 100 mg/mL, or between about 50 mg/mL and about 100mg/mL. The concentration may at least about 20 mg/mL, at least about 30mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, at least about60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at leastabout 90 mg/mL, or at least about 100 mg/mL. The concentration may beless than about 20 mg/mL, less than about 30 mg/mL, less than about 40mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, less thanabout 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL, orless than about 100 mg/mL. The concentration may be more than about 20mg/mL, more than about 30 mg/mL, more than about 40 mg/mL, more thanabout 50 mg/mL, more than about 60 mg/mL, more than about 70 mg/mL, morethan about 80 mg/mL, more than about 90 mg/mL, more than about 100mg/mL, more than about 150 mg/mL, or more than about 200 mg/mL.

The compound of Formula (III) may be released from the depot formulationat a rate providing an average plasma concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione(atovaquone) of at least about 5 μM over a period of about 13 weeks. Theaverage plasma concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be at least about 5 μM, at least about 4.5 μM, at least about 4 μM,at least about 3.5 μM, at least about 3 μM, at least about 2.5 μM, atleast about 2 μM, at least about 1.5 μM, at least about 1 μM, at leastabout 900 nM, at least about 800 nM, at least about 700 nM, at leastabout 600 nM, at least about 500 nM, at least about 400 nM, at leastabout 300 nM, at least about 200 nM, at least about 100 nM, at leastabout 95 nM, at least about 90 nM, at least about 85 nM, at least about80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM,at least about 60 nM, at least about 55 nM, at least about 50 nM, atleast about 45 nM, at least about 40 nM, at least about 35 nM, at leastabout 30 nM, at least about 25 nM, or at least about 20 nM over a periodof about 13 weeks, over a period of about 12 weeks, about 11 weeks,about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, orabout 1 week. The average plasma concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be at least about 100 nM over a period of about 4 weeks uponadministration of a compound of Formula (III).

The compound of Formula (III) may be3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate and may bereleased from the depot formulation at a rate providing an averageplasma concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione(atovaquone) of at least about 2 μM over a period of about 13 weeks. Theaverage plasma concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be at least about 2 μM, about 1.9 μM, about 1.8 μM, about 1.7 μM,about 1.6 μM, about 1.5 μM, about 1.4 μM, about 1.3 μM, about 1.2 μM,about 1.1 μM, about 1 μM, at least about 900 nM, at least about 800 nM,at least about 700 nM, at least about 600 nM, at least about 500 nM, atleast about 400 nM, at least about 300 nM, at least about 200 nM, atleast about 100 nM, at least about 95 nM, at least about 90 nM, at leastabout 85 nM, at least about 80 nM, at least about 75 nM, at least about70 nM, at least about 65 nM, at least about 60 nM, at least about 55 nM,at least about 50 nM, at least about 45 nM, at least about 40 nM, atleast about 35 nM, at least about 30 nM, at least about 25 nM, or atleast about 20 nM over a period of about 13 weeks, about 12 weeks, about11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks,about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2weeks, or about 1 week. The average plasma concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be at least about 1000 nM over a period of about 13 weeks uponadministration of3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate.

Nanoparticles or Microparticle Suspension

The compounds disclosed herein may be formulated as nanoparticle ormicroparticle suspensions. The pharmaceutical suspensions describedherein comprise nanoparticles or microparticles of a crystallinecompound disclosed herein and suitable excipients.

Nanoparticles are submicroscopic solid particles with size ranging fromabout 10 nm to about 1000 nm or from about 50 nm to about 1000 nm. Theaverage particle size of the nanoparticles describe herein may be belowabout 1000 nm, or below about 900 nm, or below about 800 nm, or belowabout 700 nm, or below about 600 nm, or below about 500 nm, or belowabout 400 nm, or below about 300 nm, or below about 200 nm, or belowabout 100 nm. The lower limit of the average particle size may be as lowas about 100 nm or as low as about 50 nm. The average particle size maybe in the range of about 50 nm to about 1000 nm, or about 50 nm to about500 nm, or about 50 nm to about 400 nm, or about 50 nm to about 300 nm,or about 50 nm to about 250 nm, or about 100 nm to about 250 nm, orabout 150 nm to about 220 nm, or 100 to 200 nm, or about 150 nm to about200 nm, e.g. about 100 nm, about 130 nm, or about 150 nm.

Microparticles are solid particles with size ranging from about 1 μm toabout 1000 μm. The average particle size of the micro particles describeherein may be below about 1000 μm, or below about 900 μm, or below about800 μm, or below about 700 μm, or below about 600 μm, or below about 500μm, or below about 400 μm, or below about 300 μm, or below about 200 μm,or below about 100 μm, or below about 90 μm, or below about 80 μm, orbelow about 70 μm, or below about 60 μm, or below about 50 μm, or belowabout 40 μm, or below about 30 μm, or below about 20 μm, or below about10 μm, or below about 5 μm, or below about 2 μm. The lower limit of theaverage particle size may be as low as about 10 μm or as low as about 5μm. The average particle size may be in the range of about 1 μm to about100 μm, or about 1 μm to about 50 μm, or about 1 μm to about 40 μm, orabout 1 μm to about 30 μm, or about 1 μm to about 20 μm, or about 1 μmto about 10 μm or about 1 μm to about 5 μm, e.g. about 1 μm, about 2 μm,about 3 μm, about 4 μm, or about 5 μm. The nanoparticle or microparticlesuspensions may be sustained or delayed release compositions of theactive ingredient that are therapeutically effective for a number ofweeks, such as at least about one week, at least about two weeks, atleast about three weeks, at least about four weeks, at least about fiveweeks, at least about six weeks, at least about seven weeks, at leastabout eight weeks, at least about nine weeks, at least ten about weeks,at least about eleven weeks, at least about twelve weeks or more. Thenanoparticle or microparticle suspensions are efficient, well-tolerated,sustained or delayed release compositions of the active ingredient thatare therapeutically effective for a number of days, such as at leastabout 5 days, at least about 10 days, at least about 15 days, at leastabout 20 days, at least about 25 days, at least about 30 days, at leastabout 35 days, at least about 40 days, at least about 45 days, at leastabout 50 days, at least about 55 days, at least about 60 days, at leastabout 65 days, at least about 70 days, at least about 75 days, at leastabout 80 days, at least about 85 days, at least about 90 days, at leastabout 95 days, at least about 100 days, at least about 105 days, atleast about 110 days, at least about 115 days, at least about 120 daysor more.

In addition to the active agent, additional ingredients may be used inthe nanoparticle or microparticle suspensions of the present inventionincluding surfactants, solubilizers, emulsifiers, preservatives,isotonicity agents, dispersing agents, wetting agents, fillers,solvents, buffers, stabilizers, lubricants, thickening agents,suspending agents, and combination thereof. The suspension may comprisea suspending agent and a surfactant. Most commonly, surfactants areclassified according to polar head group. A non-ionic surfactant has nocharged groups in its head. The head of an ionic surfactant carries anet positive, or negative charge. If the charge is negative, thesurfactant is more specifically called anionic; if the charge ispositive, it is called cationic. If a surfactant contains a head withtwo oppositely charged groups, it is termed zwitterionic. Anionicsurfactants contain anionic functional groups at their head, such assulfate, sulfonate, phosphate, and carboxylates. Prominent alkylsulfates include ammonium lauryl sulfate, sodium lauryl sulfate (sodiumdodecyl sulfate, SLS, or SDS), and the related alkyl-ether sulfatessodium laureth sulfate (sodium lauryl ether sulfate or SLES), and sodiummyreth sulfate. Others include: docusate (dioctyl sodiumsulfosuccinate), perfluorooctanesulfonate (PFOS),perfluorobutanesulfonate, alkyl-aryl ether phosphates, alkyl etherphosphates. Cationic surfactant include pH-dependent primary, secondary,or tertiary amines such as octenidine dihydrochloride; and permanentlycharged quaternary ammonium salts such as cetrimonium bromide (CTAB),cetylpyridinium chloride (CPC), benzalkonium chloride (BAC),benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, anddioctadecyldimethylammonium bromide (DODAB). Zwitterionic (amphoteric)surfactants have both cationic and anionic centers attached to the samemolecule. The cationic part is based on primary, secondary, or tertiaryamines or quaternary ammonium cations. The anionic part can be morevariable and include sulfonates, as in the sultaines CHAPS(3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate) andcocamidopropyl hydroxysultaine. Betaines such as cocamidopropyl betainehave a carboxylate with the ammonium. The most common biologicalzwitterionic surfactants have a phosphate anion with an amine orammonium, such as the phospholipids phosphatidylserine,phosphatidylethanolamine, phosphatidylcholine, and sphingomyelins.Nonionic surfactants include fatty alcohols, cetyl alcohol, stearylalcohol, and cetostearyl alcohol, and oleyl alcohol. Also used asnonionic surfactants are polyethylene glycol alkyl ethers (such asoctaethylene glycol monododecyl ether, pentaethylene glycol monododecylether), polypropylene glycol alkyl ethers, glucoside alkyl ethers (suchas decyl glucoside, lauryl glucoside, octyl glucoside), polyethyleneglycol octylphenyl ethers (such as Triton X-100), polyethylene glycolalkylphenyl ethers (such as nonoxynol-9), glycerol alkyl esters (such asglyceryl laurate), polyoxyethylene glycol sorbitan alkyl esters (such aspolysorbate, i.e., polysorbate 20 and polysorbate 80), sorbitan alkylesters (such as Spans), cocamide MEA, cocamide DEA, dodecyldimethylamineoxide, triblock copolymer comprising blocks of polyethylene glycol andblocks of polypropylene glycol such as poly(ethyleneglycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (suchas poloxamers), and polyethoxylated tallow amine (POEA). The suspensionmay comprise between about 0.1 wt % and about 10 wt % of a surfactant.The suspension may comprise between about 0.5 wt % and about 5 wt % of asurfactant. The suspension may comprise between about 1 wt % and about 4wt % of a surfactant. The suspension may comprise between about 2 wt %and about 4 wt % of a surfactant. The suspension may comprise betweenabout 3 wt % of a surfactant. The suspension may comprise a nonionicsurfactant. The nonionic surfactant may comprise polyethylene glycol.The nonionic surfactant may be a triblock copolymer comprising blocks ofpolyethylene glycol and blocks of polypropylene glycol such aspoly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethyleneglycol). The non-ionic surfactant may be Synperonic® F108. The non-ionicsurfactant may be Pluronic®. The nonionic surfactant may be a vitaminderivative, such as vitamin E derivative. The nonionic surfactant may bean esterification product of vitamin E succinate with polyethyleneglycol. The nonionic surfactant may be an esterification product ofvitamin E succinate with polyethylene glycol 1000. The non-ionicsurfactant may be D-α-tocopheryl polyethylene glycol succinate. Thenon-ionic surfactant may be D-α-tocopheryl polyethylene glycol 1000succinate (TPGS). The suspension may comprise an anionic surfactant. Theanionic surfactant may be dodecyl sodium sulfate (SLS). The suspensionmay comprise a suspending agent. The suspension may comprise betweenabout 0.1 wt % and about 10 wt % of a suspending agent. The suspensionmay comprise between about 0.5 wt % and about 5 wt % of a suspendingagent. The suspension may comprise between about 0.5 wt % and about 2 wt% of a suspending agent. The suspension may comprise between about 0.5wt % and about 1.5 wt % of a suspending agent. The suspension maycomprise about 1 wt % of a suspending agent. The suspending agent may beselected from acacia, agar, alginic acid, bentonite, calcium stearate,carbomers, cellulose or cellulose derivatives (such ascarboxymethylcellulose calcium, carboxymethylcellulose sodium,hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose),carrageenan, ceratonia, colloidal silicon dioxide, dextrin, gelatin,guar gum, kaolin, magnesium aluminum silicate, maltitol, medium-chaintriglycerides, microcrystalline cellulose, microcrystalline celluloseand carboxymethylcellulose sodium, polycarbophil, polyethylene glycol,potassium alginate, povidone, propylene glycol alginate, sesame oil,sodium alginate, sodium starch glycolate, sorbitan esters, sucrose,tragacanth, and xanthan gum. The suspending agent may be a cellulosederivative. The suspension may comprise hydroxypropyl methylcellulose(HPMC). The suspension may comprise one or more of Synperonic® F108,dodecyl sodium sulfate (SLS), or D-α-tocopheryl polyethylene glycol 1000succinate (TPGS). The suspension may comprise one or more of Synperonic®F108, dodecyl sodium sulfate (SLS), D-α-tocopheryl polyethylene glycol1000 succinate (TPGS), or hydroxypropyl methylcellulose (HPMC). Thesuspension may comprise D-α-tocopheryl polyethylene glycol 1000succinate (TPGS) and hydroxypropyl methylcellulose (HPMC).

The nanoparticles or microparticle described herein may be prepared bymeans of micronization/particle size reduction/nanonization bymechanical means. The nanoparticles or microparticle may be prepared bydry milling. The nanoparticles or microparticle may be prepared by wetmilling.

The pharmaceutical suspension may comprise crystalline6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-oneor pharmaceutically acceptable salt, solvate, or stereoisomer thereof(such as ELQ-300-Form IA, ELQ-300-Form IB, ELQ-300-Form II, ELQ-300-FormIII, ELQ-300-Form IV, or ELQ-300-Form V). The pharmaceutical suspensionmay comprise ELQ-300-Form II. The concentration of crystalline6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one,or pharmaceutically acceptable salt, solvate, or stereoisomer thereof inthe suspension may be between about 20 mg/mL and about 500 mg/mL,between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL andabout 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, betweenabout 20 mg/mL and about 100 mg/mL, or between about 50 mg/mL and about100 mg/mL. The concentration may be at least about 20 mg/mL, at leastabout 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, atleast about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL,at least about 90 mg/mL, or at least about 100 mg/mL. The concentrationmay be less than about 20 mg/mL, less than about 30 mg/mL, less thanabout 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, lessthan about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL,or less than about 100 mg/mL.

In some aspects,6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-oneis released from the suspension at a rate providing an average plasmaconcentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one(ELQ-300) of at least about 3 μM over a period of about 12 weeks. Theaverage plasma concentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be at least about 3 μM, at least about 2.5 μM, at least about 2 μM,at least about 1.5 μM, at least about 1 μM, at least about 900 nM, atleast about 800 nM, at least about 700 nM, at least about 600 nM, atleast about 500 nM, at least about 400 nM, at least about 300 nM, atleast about 200 nM, at least about 100 nM, at least about 95 nM, atleast about 90 nM, at least about 85 nM, at least about 80 nM, at leastabout 75 nM, at least about 70 nM, at least about 65 nM, at least about60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM,at least about 40 nM, at least about 35 nM, at least about 30 nM, atleast about 25 nM, or at least about 20 nM over a period of about 12weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks,about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3weeks, about 2 weeks, or about 1 week. The average plasma concentrationof6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be at least about 500 nM over a period of about 4 weeks.

The pharmaceutical suspension may comprise crystallinetrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione,or pharmaceutically acceptable salt, solvate, or stereoisomer thereof(such as atovaquone-Form I or atovaquone-Form II). The pharmaceuticalsuspension may comprise atovaquone-Form II. The concentration ofcrystallinetrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione,or pharmaceutically acceptable salt, solvate, or stereoisomer thereof inthe suspension may be between about 20 mg/mL and about 500 mg/mL,between about 20 mg/mL and about 400 mg/mL, between about 20 mg/mL andabout 300 mg/mL, between about 20 mg/mL and about 200 mg/mL, betweenabout 20 mg/mL and about 100 mg/mL, or between about 50 mg/mL and about100 mg/mL. The concentration may be at least about 20 mg/mL, at leastabout 30 mg/mL, at least about 40 mg/mL, at least about 50 mg/mL, atleast about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL,at least about 90 mg/mL, or at least about 100 mg/mL. The concentrationmay be less than about 20 mg/mL, less than about 30 mg/mL, less thanabout 40 mg/mL, less than about 50 mg/mL, less than about 60 mg/mL, lessthan about 70 mg/mL, less than about 80 mg/mL, less than about 90 mg/mL,or less than about 100 mg/mL.

In some aspects,trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione isreleased from the suspension at a rate providing an average plasmaconcentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione(atovaquone) of at least about 5 μM over a period of about 12 weeks. Theaverage plasma concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be at least about 5 μM, at least about 4.5 μM, at least about 4 μM,at least about 3.5 μM, at least about 3 μM, at least about 2.5 μM, atleast about 2 μM, at least about 1.5 μM, at least about 1 μM, at leastabout 900 nM, at least about 800 nM, at least about 700 nM, at leastabout 600 nM, at least about 500 nM, at least about 400 nM, at leastabout 300 nM, at least about 200 nM, at least about 100 nM, at leastabout 95 nM, at least about 90 nM, at least about 85 nM, at least about80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM,at least about 60 nM, at least about 55 nM, at least about 50 nM, atleast about 45 nM, at least about 40 nM, at least about 35 nM, at leastabout 30 nM, at least about 25 nM, or at least about 20 nM over a periodof about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks,about 3 weeks, about 2 weeks, or about 1 week. The average plasmaconcentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be at least about 3 μM over a period of about 4 weeks.

The pharmaceutical suspension may comprise crystalline(6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methylbutyrate (compound 2), or pharmaceutically acceptable salt, solvate, orstereoisomer thereof. The concentration of crystalline(6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methylbutyrate, or pharmaceutically acceptable salt, solvate, or stereoisomerthereof in the suspension may be between about 20 mg/mL and about 500mg/mL, between about 20 mg/mL and about 400 mg/mL, between about 20mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200 mg/mL,between about 20 mg/mL and about 100 mg/mL, or between about 50 mg/mLand about 100 mg/mL. The concentration may be at least about 20 mg/mL,at least about 30 mg/mL, at least about 40 mg/mL, at least about 50mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL. Theconcentration may be less than about 20 mg/mL, less than about 30 mg/mL,less than about 40 mg/mL, less than about 50 mg/mL, less than about 60mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, less thanabout 90 mg/mL, or less than about 100 mg/mL.

In some aspects,(6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methylbutyrate is released from the suspension at a rate providing an averageplasma concentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one(ELQ-300) of at least about 3 μM over a period of about 12 weeks. Theaverage plasma concentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be at least about 3 μM, at least about 2.5 μM, at least about 2 μM,at least about 1.5 μM, at least about 1 μM, at least about 900 nM, atleast about 800 nM, at least about 700 nM, at least about 600 nM, atleast about 500 nM, at least about 400 nM, at least about 300 nM, atleast about 200 nM, at least about 100 nM, at least about 95 nM, atleast about 90 nM, at least about 85 nM, at least about 80 nM, at leastabout 75 nM, at least about 70 nM, at least about 65 nM, at least about60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM,at least about 40 nM, at least about 35 nM, at least about 30 nM, atleast about 25 nM, or at least about 20 nM over a period of about 12weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks,about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3weeks, about 2 weeks, or about 1 week.

The pharmaceutical suspension may comprise crystalline compounds ofFormula (II), or pharmaceutically acceptable salt, solvate, orstereoisomer thereof. The concentration of crystalline compounds ofFormula (II), or pharmaceutically acceptable salt, solvate, orstereoisomer thereof in the suspension may be between about 20 mg/mL andabout 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, betweenabout 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200mg/mL, between about 20 mg/mL and about 100 mg/mL, or between about 50mg/mL and about 100 mg/mL. The concentration may be at least about 20mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at leastabout 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL.The concentration may be less than about 20 mg/mL, less than about 30mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less thanabout 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, lessthan about 90 mg/mL, or less than about 100 mg/mL.

In some aspects, the crystalline compound of Formula (II), orpharmaceutically acceptable salt, solvate, or stereoisomer thereof isreleased from the suspension at a rate providing an average plasmaconcentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one(ELQ-300) of at least about 3 μM over a period of about 12 weeks. Theaverage plasma concentration of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be at least about 3 μM, at least about 2.5 μM, at least about 2 μM,at least about 1.5 μM, at least about 1 μM, at least about 900 nM, atleast about 800 nM, at least about 700 nM, at least about 600 nM, atleast about 500 nM, at least about 400 nM, at least about 300 nM, atleast about 200 nM, at least about 100 nM, at least about 95 nM, atleast about 90 nM, at least about 85 nM, at least about 80 nM, at leastabout 75 nM, at least about 70 nM, at least about 65 nM, at least about60 nM, at least about 55 nM, at least about 50 nM, at least about 45 nM,at least about 40 nM, at least about 35 nM, at least about 30 nM, atleast about 25 nM, or at least about 20 nM over a period of about 12weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks,about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3weeks, about 2 weeks, or about 1 week.

The pharmaceutical suspension may comprise crystalline compounds ofFormula (III), or pharmaceutically acceptable salt, solvate, orstereoisomer thereof. The concentration of crystalline compounds ofFormula (III), or pharmaceutically acceptable salt, solvate, orstereoisomer thereof in the suspension may be between about 20 mg/mL andabout 500 mg/mL, between about 20 mg/mL and about 400 mg/mL, betweenabout 20 mg/mL and about 300 mg/mL, between about 20 mg/mL and about 200mg/mL, between about 20 mg/mL and about 100 mg/mL, or between about 50mg/mL and about 100 mg/mL. The concentration may be at least about 20mg/mL, at least about 30 mg/mL, at least about 40 mg/mL, at least about50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at leastabout 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL.The concentration may be less than about 20 mg/mL, less than about 30mg/mL, less than about 40 mg/mL, less than about 50 mg/mL, less thanabout 60 mg/mL, less than about 70 mg/mL, less than about 80 mg/mL, lessthan about 90 mg/mL, or less than about 100 mg/mL.

In some aspects, the crystalline compound of Formula (III), orpharmaceutically acceptable salt, solvate, or stereoisomer thereof isreleased from the suspension at a rate providing an average plasmaconcentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione(atovaquone) of at least about 5 μM over a period of about 12 weeks. Theaverage plasma concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be at least about 5 μM, at least about 4.5 μM, at least about 4 μM,at least about 3.5 μM, at least about 3 μM, at least about 2.5 μM, atleast about 2 μM, at least about 1.5 μM, at least about 1 μM, at leastabout 900 nM, at least about 800 nM, at least about 700 nM, at leastabout 600 nM, at least about 500 nM, at least about 400 nM, at leastabout 300 nM, at least about 200 nM, at least about 100 nM, at leastabout 95 nM, at least about 90 nM, at least about 85 nM, at least about80 nM, at least about 75 nM, at least about 70 nM, at least about 65 nM,at least about 60 nM, at least about 55 nM, at least about 50 nM, atleast about 45 nM, at least about 40 nM, at least about 35 nM, at leastabout 30 nM, at least about 25 nM, or at least about 20 nM over a periodof about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks,about 3 weeks, about 2 weeks, or about 1 week.

Methods of Treatment and Treatment Regiments

Described herein are methods for the treatment or prevention of malaria.

Described herein are methods for the treatment or prevention of malaria,comprising administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof to a subject in need thereof.

Described herein are methods for the treatment or prevention of malaria,comprising administering a pharmaceutical composition comprising an oiland a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof to a subject in need thereof. Thecompound of Formula (II) may be((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate.

Described herein are methods for the treatment or prevention of malaria,comprising administering a pharmaceutical composition comprising an oiland a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof to a subject in need thereof. Thecompound of Formula (III) may be3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate.

Described herein are methods for the treatment or prevention of malaria,comprising administering a pharmaceutical suspension comprisingnanoparticles or microparticles of a crystalline form of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofto a subject in need thereof. The crystalline form of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be ELQ-300-Form IA. The crystalline form of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be ELQ-300-Form IB. The crystalline form of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be ELQ-300-Form II. The crystalline form of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be ELQ-300-Form III. The crystalline form of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be ELQ-300-Form IV. The crystalline form of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-onemay be ELQ-300-Form V.

Described herein are methods for the treatment or prevention of malaria,comprising administering a pharmaceutical suspension comprisingnanoparticles or microparticles of a crystalline compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof to a subject in need thereof. The crystalline compound ofFormula (II) may be crystalline6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-ylpropionate. The crystalline compound of Formula (II) may be6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-ylethyl carbonate. The crystalline compound of Formula (II) may be(6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methylbutyrate.

Described herein are methods for the treatment or prevention of malaria,comprising administering a pharmaceutical suspension comprisingnanoparticles or microparticles of a crystalline form oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofto a subject in need thereof. The crystalline form oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be atovaquone-Form I. The crystalline form oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedionemay be atovaquone-Form II.

Described herein are methods for the treatment or prevention of malaria,comprising administering a pharmaceutical suspension comprisingnanoparticles or microparticles of a crystalline compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof to a subject in need thereof. The crystalline compound ofFormula (III) may be crystalline3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yldecanoate.

Described herein are methods for the treatment or prevention of malaria,comprising administering a pharmaceutical suspension comprisingnanoparticles or microparticles of a crystalline form of4-(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-1-ylmethyl)phenol,or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofto a subject in need thereof. The crystalline form of4-(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-1-ylmethyl)phenolmay be pyronaridine-Form I. The crystalline form of4-(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-1-ylmethyl)phenolmay be pyronaridine-Form II. The crystalline form of4-(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-1-ylamino)-2,6-bis(pyrrolidin-1-ylmethyl)phenolmay be pyronaridine-Form III. The crystalline form of4-(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-1-ylmethyl)phenolmay be pyronaridine-Form IV. The crystalline form of4-(7-chloro-2-methoxybenzo[b][1,5]naphthyridin-10-ylamino)-2,6-bis(pyrrolidin-1-ylmethyl)phenolmay be pyronaridine-Form V.

In some embodiments of any of the foregoing methods, the malaria is drugresistant (e.g., the malaria is resistant to chloroquine, quinine,pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine,artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil,doxycycline, clindamycin, artemisinin, atovaquone, or any combinationthereof). The malaria may be liver stage.

The compounds described herein may be useful in any of the foregoingmethods and, while not bound by theory, are believed to exert theirdesirable effects through their ability to inhibit the growth of or killthe parasitic protozoan which causes malaria (e.g., P. falciparum, P.vivax, P. ovale, P. malariae, P. knowlesi). The treatment of malaria mayincludes causative prophylaxis, such as preventing the spread ofplasmodium infection beyond the liver, preventing systemic disease,preventing the symptomatic stage of malaria, and/or preventing theestablishment of the infection. The treatment of malaria may refers totreatment intended to achieve cure (e.g., of P. vivax or P. malariae),e.g., treatment for radical cure (i.e., clearing hypnozoites from theliver). The methods may include preventing spread of infection of amalaria-causing parasite as described herein from the liver.

The pharmaceutical compositions and the pharmaceutical suspensioncontaining the compound(s) described herein may be administered forprophylactic and/or therapeutic treatments. In certain therapeuticapplications, the pharmaceutical compositions and pharmaceuticalsuspensions are administered to a patient already suffering frommalaria, in an amount sufficient to cure or at least partially arrest atleast one of the symptoms of malaria. Amounts effective for this usedepend on the severity and course of the disease or condition, previoustherapy, the patient's health status, weight, and response to the drugs,and the judgment of the treating physician. Therapeutically effectiveamounts are optionally determined by methods including, but not limitedto, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, pharmaceutical compositions andpharmaceutical suspensions containing the compounds described herein areadministered to a patient susceptible to or otherwise at risk ofdeveloping malaria. Such an amount is defined to be a “prophylacticallyeffective amount or dose.” In this use, the precise amounts also dependon the patient's state of health, weight, and the like. When used inpatients, effective amounts for this use will depend on the severity andcourse of the disease, disorder or condition, previous therapy, thepatient's health status and response to the drugs, and the judgment ofthe treating physician. In one aspect, prophylactic treatments includeadministering to a mammal, who previously experienced at least onesymptom of the disease being treated and is currently in remission, apharmaceutical composition comprising a compound described herein, or apharmaceutically acceptable salt thereof, in order to prevent a returnof the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.1 mg-100 mg per day. In one aspect, dosesemployed for adult human treatment are from about 0.5 mg to about 10 mgper day. The pharmaceutical composition or pharmaceutical suspension maybe formulated to deliver from about 0.5 mg to about 10 mg per day forabout 90 days. The pharmaceutical composition or pharmaceuticalsuspension may be formulated to deliver about 0.5 mg, about 0.6 mg,about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg,about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg,about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg,about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg,about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg,about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg,about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg,about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg,about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg,about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg,about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg,about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg,about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg,about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg,about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8 mg, about 8.1 mg,about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg,about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9 mg, about 9.1 mg,about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg,about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10 mg per day forabout 90 days, about 80 days, about 70 days, about 60 days, about 50days, about 40 days, about 30 days, about 20 days, or about 10 days. Thepharmaceutical composition or pharmaceutical suspension may beformulated to deliver from about 0.5 mg to about 10 mg per day for about120 days. The pharmaceutical composition or pharmaceutical suspensionmay be formulated to deliver from about 0.5 mg to about 10 mg per dayfor about 120 days, about 115 days, about 110 days, about 105 days,about 100 days, about 95 days, about 90 days, about 85 days, about 80days, about 75 days, about 70 days, about 65 days, about 60 days, about55 days, about 50 days, about 45 days, about 40 days, about 35 days,about 30 days, about 25 days, about 20 days, about 15 days, or about 10days.

In one embodiment, the dosages appropriate for the compound describedherein, or a pharmaceutically acceptable salt thereof, are from about0.01 to about 100 mg/kg per body weight. In one aspect, the dosage isfrom about 5 to about 50 mg/kg, or about 5 mg/kg, about 10 mg/kg, about15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg,about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, or about 100mg/kg.

The daily dosage or the amount of active in the dosage form may be loweror higher than the ranges indicated herein, based on a number ofvariables in regard to an individual treatment regime. In variousembodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Thedaily dosage amount of the compounds described herein may lie within arange of circulating concentrations that include the ED₅₀ with minimaltoxicity. In certain embodiments, the daily dosage range and/or the unitdosage amount varies within this range depending upon the dosage formemployed and the route of administration utilized.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, the benefit experienced by a patient may beincreased by administering one of the compounds described herein withanother agent (which also includes a therapeutic regimen) that also hastherapeutic benefit. The other agent may be an additional antimalarialagent. The additional antimalarial agent may be artemisinin, artemisininderivatives, atovaquone, proguanil, quinine, chloroquine, amodiaquine,pyrimethamine, doxycycline, clindamycin, mefloquine, primaquine,pyronaridine, halofantrine, or ELQ-300.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may be additiveof the two therapeutic agents or the patient may experience asynergistic benefit.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g. the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, deviates from the dosageregimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

The compounds described herein, or a pharmaceutically acceptable saltthereof, as well as combination therapies, are administered before,during or after the occurrence of a disease or condition, and the timingof administering the composition containing a compound varies. Thus, inone embodiment, the compounds described herein are used as aprophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. The length required for treatment may vary, and the treatmentlength is adjusted to suit the specific needs of each subject. Forexample, in specific embodiments, a compound described herein or aformulation containing the compound is administered for at least 2weeks, about 1 month to about 5 years.

EXAMPLES

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Example 1: General Procedure for the Preparation of Compounds 1-5, 7-11,and 35

6-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one(1 equiv), Cs₂CO₃ (3 equiv), and anhydrous DMF (0.1 M) were added to avial followed by the appropriate chloromethylester (3 equiv). Themixture was allowed to stir at 80° C. overnight. After that, thereaction was quenched with saturated aqueous NH₄Cl solution, extractedwith EtOAc, and washed with brine. The organic layers were combined,dried under Na₂SO₄, filtered, and concentrated under reduced pressure.The crude material was submitted to silica gel column chromatography toafford the desired products (eluent hexanes→hexanes:EtOAc=4:1) as whitesolids.

Example 2: General Procedure for the Preparation of Compounds 12-19

A suspension of6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one(1 equiv) and NaH (2 equiv) in anhydrous THF (0.1 M) was stirred at 80°C. for 1 h. After cooling the reaction mixture to ambient temperaturethe appropriate chloroformate were added (2 equiv). The reaction mixturewas then stirred at 80° C. for 2 h. After that, the reaction wasquenched with saturated aqueous NH₄Cl solution, extracted with EtOAc,and washed with brine. The organic layers were combined, dried underNa₂SO₄, filtered, and concentrated under reduced pressure. The crudematerial was submitted to silica gel column chromatography to afford thedesired products (eluent hexanes→hexanes:EtOAc=4:1) as white solids.

Example 3: General Procedure for the Preparation of Compounds 20-33

To a suspension oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione (1equiv) and K₂CO₃ (2 equiv) in anhydrous CH₃CN (0.1 M) was added theappropriate acid chloride (3.5 equiv). The reaction mixture stirred for10 hours at 80° C. Upon completion, the reaction was cooled to ambienttemperature and quenched with water, extracted with EtOAc, and washedwith brine. The organic layers were combined, dried under Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas submitted to silica gel column chromatography to afford the desiredproducts (eluent hexanes→hexanes:EtOAc=19:1) as yellow solids.

Analytical data are presented in table 3.

TABLE 3 Cmpd. Characterization Data (NMR and LCMS) 2 ¹H NMR (400 MHz,CDCl₃) δ 8.06 (s, 1H), 7.47 (s, 1H), 7.41-7.36 (m, 2H), 7.26 (d, mz,2H), 7.17-7.10 (m, 4H), 5.31 (s, 2H), 4.06 (s, 3H), 2.54 (s, 3H), 2.17(t, J = 7.4 Hz, 2H), 1.54 (sex, J = 7.4 Hz, 2H), 0.85 (t, J = 7.4 Hz,3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −58.24 (s, 3F). MS-ESI: m/z 576.14observed (M + H)⁺ 3 ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.52 (s,1H), 7.42-7.36 (m, 2H), 7.27 (m, 2H), 7.18-7.09 (m, 4H), 5.30 (s, 2H),4.07 (s, 3H), 2.56 (s, 3H), 2.43 (sept, J = 7.0 Hz, 1H), 1.06 (d, J =7.0 Hz, 6H). ¹⁹F NMR (376 MHz, CDCl₃) δ −58.23. MS-ESI: m/z 576.15observed (M + H)⁺ 4 ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.49 (s,1H), 7.40-7.36 (m, 2H), 7.28-7.24 (m, 2H), 7.18-7.10 (m, 4H), 5.31 (s,2H), 4.06 (s, 3H), 2.54 (s, 3H), 2.17 (t, J = 7.6 Hz, 2H), 1.48 (p, J =7.5 Hz, 2H), 1.28-1.1 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H). ¹⁹F NMR (376MHz, CDCl₃) δ −58.24 (s, 3F). MS-ESI: m/z 604.16 observed (M + H)⁺ 8 ¹HNMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 7.48 (s, 1H), 7.41-7.35 (m, 2H),7.30-7.23 (m, 2H), 7.18-7.07 (m, 4H), 5.31 (s, 2H), 4.07 (s, 3H), 2.55(s, 3H), 2.18 (t, J = 7.6 Hz, 2H), 1.54-1.43 (m, 2H), 1.33-1.12 (m,12H), 0.89 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −58.24 (s,3F). MS-ESI: m/z 659.83 observed (M + H)⁺ 9 ¹H NMR (400 MHz, CDCl₃) δ8.06 (s, 1H), 7.48 (s, 1H), 7.41-7.26 (m, 2H), 7.31-7.23 (m, 2H),7.19-7.09 (m, 4H), 5.31 (s, 2H), 4.07 (s, 3H), 2.55 (s, 3H), 2.18 (t, J= 7.5 Hz, 2H), 1.53-1.40 (m, 2H), 1.36-1.12 (m, 20H), 0.89 (t, J = 6.7Hz, 3H). MS-ESI: m/z 716.29 observed (M + H)⁺ 10 ¹H NMR (400 MHz, CDCl₃)δ 8.06 (s, 1H), 7.47 (s, 1H), 7.41-7.35 (m, 2H), 7.30-7.23 (m, 2H),7.17-7.10 (m, 4H), 5.31 (s, 2H), 4.06 (s, 3H), 2.55 (s, 3H), 2.18 (t, J= 7.5 Hz, 2H), 1.54-1.44 (m, 2H), 1.34-1.13 (m, 24H), 0.89 (t, J = 6.8Hz, 4H). ¹⁹F NMR (376 MHz, CDCl₃) δ −58.24 (s, 3F). MS-ESI: m/z 745.30observed (M + H)⁺ 12 ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s, 1H), 7.53 (s,1H), 7.32-7.22 (m, 4H), 7.15-7.06 (m, 4H), 4.07 (s, 3H), 3.77 (s, 3H),2.55 (s, 3H). MS-ESI: m/z 534.04 observed (M + H)⁺ 13 ¹H NMR (400 MHz,CDCl₃) δ 7.91 (s, 1H), 7.55 (s, 1H), 7.35-7.18 (m, 4H), 7.15-7.07 (m,4H), 4.18 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 2.57 (s, 3H), 1.24 (t, J =7.1 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ −58.25 (s, 3F). MS-ESI: m/z548.10 observed (M + H)⁺ 14 ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.55(s, 1H), 7.34-7.22 (m, 4H), 7.15-7.05 (m, 4H), 4.12-4.05 (m, 5H), 2.57(s, 3H), 1.62 (sex, J = 7.2, 2H), 0.90 (t, J = 7.4 Hz, 4H). ¹⁹F NMR (376MHz, CDCl₃) δ −58.25 (s, 3F). MS-ESI: m/z 562.11 observed (M + H)⁺ 15 ¹HNMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.51 (s, 1H), 7.34-7.29 (m, 2H),7.26-7.20 (m, 2H), 7.13-7.05 (m, 4H), 4.80 (sept, J = 6.3 Hz, 1H), 4.07(s, 3H), 2.55 (s, 3H), 1.22 (d, J = 62 Hz, 6H). ¹⁹F NMR (376 MHz, CDCl₃)δ −58.25 (s, 3F). MS-ESI: m/z 562.11 observed (M + H)⁺ 16 ¹H NMR (400MHz, CDCl₃) δ 7.90 (s, 1H), 7.52 (s, 1H), 7.36-7.21 (m, 4H), 7.18-7.04(m, 4H), 4.12 (t, J = 6.7 Hz, 2H), 4.08 (s, 3H), 1.58 (p, J = 6.7 Hz,3H), 1.38-1.22 (m, 6H), 0.91 (t, J = 6.9 Hz, 3H). MS-ESI: m/z 604.16observed (M + H)⁺ 17 ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s, 1H), 7.50 (s,1H), 7.34-7.27 (m, 2H), 7.26-7.22 (m, 2H), 7.14-7.05 (m, 4H), 4.10 (t, J= 6.7 Hz, 2H), 4.06 (s, 3H), 2.55 (s, 3H), 1.62- 1.51 (m, 2H), 1.34-1.22(m, 14H), 0.92-0.89 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ−58.27 (s, 3F). MS-ESI: m/z 659.89 observed (M + H)⁺ 18 ¹H NMR (400 MHz,CDCl₃) δ 7.88 (s, 1H), 7.49 (s, 1H), 7.34-7.17 (m, 4H), 7.15-7.04 (m,4H), 4.10 (t, J = 6.7 Hz, 2H), 4.06 (s, 3H), 2.55 (s, 3H), 1.57 (s, 2H),1.34-1.22 (m, 26H), 0.88 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (376 MHz, CDCl₃) δ−58.26 (s, 3F). MS-ESI: m/z 743.98 observed (M + H)⁺ 20 ¹H NMR (400 MHz,CDCl₃) δ 8.16-8.10 (m, 1H), 8.10-8.06 (m, 1H), 7.79-7.69 (m, 2H),7.31-7.26 (m, 2H), 7.21-7.14 (m, 2H), 3.08 (tt, J = 12.3, 3.5 Hz, 1H),2.60 (tt, J = 12.3, 3.3 Hz, 1H), 2.46 (s, 3H), 2.07-1.93 (m, 4H),1.88-1.78 (m, 2H), 1.61-1.48 (m, 2H). 21 ¹H NMR (400 MHz, Chloroform-d)δ 8.19-8.13 (m, 1H), 8.10 (dd, J = 7.2, 1.8 Hz, 1H), 7.83-7.71 (m, 2H),7.30 (d, J = 8.8 Hz, 3H), 7.24-7.17 (m, 2H), 3.27-3.01 (m, 1H), 2.80 (q,J = 7.5 Hz, 2H), 2.62 (t, J = 12.1 Hz, 1H), 2.04 (dd, J = 15.4, 11.7 Hz,5H), 1.91- 1.78 (m, 2H), 1.39 (t, J = 7.5 Hz, 3H). 22 ¹H NMR (400 MHz,CDCl₃) δ 8.14-8.10 (m, 1H), 8.10-8.06 (m, 1H), 7.78-7.69 (m, 2H), 7.27(d, J = 8.5 Hz, 2H), 7.20-7.13 (m, 2H), 3.13-3.03 (m, 1H), 2.71 (t, J =7.4 Hz, 2H), 2.59 (t, J = 12.3 Hz, 1H), 2.08-1.94 (m, 5H), 1.92-1.77 (m,4H), 1.53 (d, J = 3.5 Hz, 1H), 1.13 (t, J = 7.4 Hz, 3H). 23 ¹H NMR (400MHz, Chloroform-d) δ 8.23-8.12 (m, 1H), 8.12-8.04 (m, 1H), 7.83- 7.70(m, 2H), 7.30 (d, J = 6.4 Hz, 2H), 7.24-7.15 (m, 2H), 3.12 (d, J = 12.3Hz, 1H), 2.59 (t, J = 12.2 Hz, 1H), 2.02 (d, J = 13.3 Hz, 3H), 1.85 (d,J = 12.1 Hz, 2H), 1.64-1.52 (m, 2H), 1.50 (s, 9H). 24 ¹H NMR (400 MHz,Chloroform-d) δ 8.18-8.12 (m, 1H), 8.12-8.06 (m, 1H), 7.81- 7.71 (m,2H), 7.30 (d, J = 8.4 Hz, 2H), 7.23-7.15 (m, 2H), 3.13 (d, J = 12.2 Hz,1H), 2.60 (t, J = 12.3 Hz, 1H), 2.02 (d, J = 12.3 Hz, 5H), 1.85 (d, J =11.4 Hz, 2H), 1.57 (m, 2H), 1.46 (d, J = 7.0 Hz, 6H). 25 ¹H NMR (400MHz, Chloroform-d) δ 8.18-8.13 (m, 1H), 8.10 (dd, J = 7.3, 1.7 Hz, 1H),7.82-7.72 (m, 2H), 7.30 (d, J = 9.5 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H),3.10 (s, 1H), 2.75 (t, J = 7.5 Hz, 2H), 2.62 (s, 1H), 2.02 (s, 4H), 1.87(q, J = 7.9 Hz, 4H), 1.56-1.52 (m, 6H), 0.99 (t, J = 7.1 Hz, 3H). 26 ¹HNMR (400 MHz, Chloroform-d) δ 8.20-8.12 (m, 1H), 8.10 (dd, J = 7.3, 1.7Hz, 1H), 7.83-7.70 (m, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.20 (td, J = 6.3,5.9, 2.3 Hz, 2H), 3.14- 3.04 (m, 1H), 2.75 (t, J = 7.5 Hz, 2H),2.68-2.56 (m, 1H), 2.02 (dd, J = 13.3, 7.7 Hz, 4H), 1.92-1.79 (m, 4H),1.69-1.47 (m, 4H), 1.05 (t, J = 7.3 Hz, 3H). 27 ¹H NMR (400 MHz, CDCl₃)δ 8.17-8.08 (m, 2H), 7.81-7.70 (m, 2H), 7.32-7.27 (m, 2H), 7.22-7.17 (m,2H), 3.18-3.03 (m, 1H), 2.78-2.72 (m, 2H), 2.67-2.57 (m, 1H), 2.11-1.96(m, 4H), 1.93-1.80 (m, 4H), 1.66-1.22 (m, 15H), 0.96-0.86 (m, 3H). 28 ¹HNMR (400 MHz, CDCl₃) δ 8.20-8.05 (m, 2H), 7.85-7.68 (m, 2H), 7.36-7.23(m, 2H), 7.23-7.09 (m, 2H), 3.18-3.00 (m, 1H), 2.75 (t, J = 7.4 Hz, 2H),2.68-2.52 (m, 1H), 2.12-1.92 (m, 4H), 1.92-1.75 (m, 4H), 1.64-1.45 (m,5H), 1.45-1.18 (m, 13H), 0.90 (t, J = 6.7 Hz, 3H). 29 ¹H NMR (400 MHz,Chloroform-d) δ 8.17-8.12 (m, 1H), 8.12-8.07 (m, 1H), 7.81- 7.67 (m,2H), 7.31 (m, 2H), 7.23-7.16 (m, 2H), 3.09 (d, J = 12.0 Hz, 1H), 2.74(t, J = 7.5 Hz, 2H), 2.62 (t, J = 12.4 Hz, 1H), 2.01 (d, J = 12.3 Hz,4H), 1.86 (q, J = 7.4 Hz, 4H), 1.67 (q, J = 7.2 Hz, 1H), 1.62-1.46 (m,6H), 1.28 (m, 19H), 0.96-0.82 (m, 3H). 30 ¹H NMR (400 MHz, Chloroform-d)δ 8.16-8.12 (m, 1H), 8.12-8.09 (m, 1H), 7.80- 7.72 (m, 2H), 7.29 (m,2H), 7.20-7.14 (m, 2H), 3.20-2.95 (m, 1H), 2.86-2.71 (m, 1H), 2.72-2.55(m, 1H), 2.22-2.06 (m, 2H), 2.01 (d, J = 11.5 Hz, 1H), 1.97-1.76 (m,4H), 1.74-1.43 (m, 9H), 1.06 (t, J = 7.1 Hz, 6H). 31 ¹H NMR (400 MHz,Chloroform-d) δ 8.18-8.12 (m, 1H), 8.12-8.07 (m, 1H), 7.81- 7.71 (m,2H), 7.30 (d, J = 8.5 Hz, 2H), 7.23-7.16 (m, 2H), 3.22-2.97 (m, 1H),2.73 (t, J = 7.4 Hz, 2H), 2.62 (t, J = 12.3 Hz, 1H), 2.06-1.96 (m, 5H),1.96-1.80 (m, 4H), 1.15 (t, J = 7.4 Hz, 3H). 32 ¹H NMR (400 MHz,Chloroform-d) δ 8.18-8.12 (m, 1H), 8.12-8.07 (m, 1H), 7.81- 7.71 (m,2H), 7.28 (m, 2H), 7.22-7.16 (m, 2H), 3.10 (m, 1H), 2.75 (t, J = 7.4 Hz,2H), 2.66-2.54 (m, 1H), 2.02 (s, 4H), 1.86 (q, J = 7.2, 6.7 Hz, 4H),1.38 (d, J = 46.6 Hz, 12H), 0.97-0.83 (m, 3H). 33 ¹H NMR (400 MHz,CDCl₃) δ 8.14-8.12 (m, 1H), 8.10-8.08 (m, 1H), 7.78-7.71 (m, 2H), 7.27(d, J = 8.5 Hz, 2H), 7.20-7.13 (m, 2H), 5.60-5.51 (m, 2H), 5.47-5.31 (m,10H), 3.16-3.08 (m, 1H), 2.96-2.82 (m, 12H), 2.67-2.59 (m, 3H),2.13-1.99 (m, 6H) 1.88-1.84 (m, 2H), 1.63-1.52 (m, 2H), 0.99 (t, J = 8.0Hz, 3H). 34 ¹H NMR (400 MHz, CDCl₃) δ 8.11-8.08 (m, 1H), 8.07-8.04 (m,1H), 7.76-7.69 (m, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.20-7.13 (m, 2H),5.52 (s, 2H), 5.45-5.29 (m, 12H), 3.82 (t, J = 8.0 Hz, 2H), 3.31-3.23(m, 1H), 2.87-2.79 (m, 10H), 2.72-2.64 (m, 1H), 2.29 (qd, J = 12.0, 4.0Hz, 2H), 2.22-2.16 (m, 2H), 2.13-2.05 (m, 2H), 2.04-1.99 (m, 2H),1.80-1.70 (m, 4H), 1.61-1.50 (m, 2H), 0.99 (t, J = 8.0 Hz, 3H). 35 ¹HNMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.45 (s, 1H), 7.37-7.35 (m, 2H),7.26-7.23 (m, 2H), 7.14-7.09 (m, 4H), 5.41-5.30 (m, 11H), 5.29 (s, 2H),5.23-5.18 (m, 1H), 4.04 (s, 3H), 2.84-2.73 (m, 10H), 2.52 (s, 3H),2.27-2.21 (m, 4H), 2.10-2.02 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); ¹⁹F NMR(376 MHz, CDCl₃) δ −58.24 (s, 3F). MS-ESI: m/z 816.10 observed (M + H)⁺

Example 5: Sesame Oil Formulation

Sesame oil (10 μL) was dispensed into compound (10 mg). The mixture wasvortexed, sonicated and warmed (using heat gun) to aid dissolution. Thesolubility of the compound was judged after the sesame oil mixturecooled to room temperature. If the compound was not completelydissolved, additional sesame oil was added in low-volume increments.

Example 6: General Methods and Materials for Solid StateCharacterization Polarized Light Microscope (PLM)

Nikon LV 100 PLM (Nikon Instruments Inc., USA) was used to examine thepresence of big crystals (typically size larger than 5 μm) in the milledcrystalline compounds suspensions. One drop of the test suspension wassmeared on a microscope slide and covered by a cover slip forexamination under crossed polarizers.

X-Ray Powder Diffraction (XRPD)

The X-ray powder diffraction patterns of all crystalline forms of thecompounds were obtained on Bruker D8 advance X-ray powderdiffractometer. Test materials were placed on monocrystalline siliconXRPD pan for analysis. The instrument specification and settings are asfollows:

Tube: Cu: K-Alpha (λ=1.54179 Å). Generator: Voltage: 40 kV; Current: 40mA. Scan Scope: 4 to 40 deg.

Sample rotation speed: 15 rpm.Scanning rate: 10 deg./min.

Differential Scanning Calorimetry (DSC)

DSC data were acquired using a TA Q2000 DSC. A sample weighted between0.5 and 1 mg was sealed into an aluminum pan with a pinhole. This panwas placed in the sample position in the calorimeter cell. An empty panwas placed in the reference position. The heating program was set toheat the sample from 30° C. to 300° C. at a rate of 10° C./min. When therun is completed, the data were analyzed using TA Universal Analysis.

Thermal Gravimetric Analysis (TGA)

TGA data were acquired using a TA Q5000 TGA. A sample weighted between 2and 5 mg was placed in an open platinum pan and heated from 25° C. to300° C. at a rate of 10° C./min. When the run is completed, the datawere analyzed using TA Universal Analysis.

Size Distribution Measurement

Size distribution of milled crystalline compound suspensions wasmeasured by Nicomp Zeta Potential & Particle Sizer 380 (Particle SizingSystems Inc., USA). One drop of a test suspension was diluted withdeionized water to a desired light scattering intensity (typically300-700 kHz) and added into the sample cell to ⅓-⅔ of the cell volume.The sample cell was left in the cell pedestal for 5 min to allowtemperature equilibration. The settings of instrument parameters are asfollows:

Intensity setpoint: 300 kHz.Fixed angle: 90°.

Temperature: 23° C.

Liquid viscosity: 0.933 CP.Liquid index of refraction: 1.333.

HPLC Method

Concentrations of the crystalline compound in suspensions weredetermined using Agilent HPLC 1200 and 1260 and the HPLC condition is asfollows:

Column Ascentis Express C18, 100 × 4.6 mm, 2.7 μm Mobile Phase A = 0.1%H₃PO₄/H₂O B = ACN Gradient A:B Initial: 90:10 6 min: 5:95 8 min: 5:95Flow rate 1.8 mL/min Gradient Time 8 min (+2 min re-equilibration)Temperature 40° C. Injection volume 10 μL Wavelength 210 nm

Example 7: Synthesis of ELQ-300 Crystalline Forms

ELQ-300 crystalline forms were prepared and characterized via DSC, XRPDand TGA. Two distinct crystalline forms of the raw material wereidentified, designated as form IA and form IB. Four new crystallineforms of ELQ-300 were identified and designated as Form II, Form III,Form IV and Form V. FIG. 5 shows the characteristic X-ray diffractionpattern of the crystalline ELQ-300-Form IA. FIG. 6 shows thecharacteristic X-ray diffraction pattern of the crystalline ELQ-300-FormIB.

Table 4 shows the characteristic reflections and the correspondingd-spacings for crystalline ELQ-300-Form IA.

TABLE 4 No. 2-Theta (°) d-spacing (Å) 1 7.65 11.55 2 8.63 10.24 3 11.467.71 4 11.96 7.39 5 12.74 6.94 6 15.79 5.61 7 16.07 5.51 8 16.45 5.38 916.96 5.22 10 17.34 5.11 11 18.67 4.75 12 19.09 4.65 13 19.72 4.50 1420.16 4.40 15 20.45 4.34 16 20.93 4.24 17 22.44 3.96 18 23.02 3.86 1924.18 3.68 20 24.73 3.60 21 25.89 3.44 22 27.27 3.27 23 28.26 3.16 2428.95 3.08 25 29.15 3.06 26 29.86 2.90 27 30.27 2.95 28 32.31 2.77 2932.74 2.73 30 36.21 2.48 31 37.77 2.38

Table 5 shows the characteristic reflections and the correspondingd-spacings for crystalline ELQ-300-Form IB.

TABLE 5 No. 2-Theta (°) d-spacing (Å) 1 5.23 16.87 2 7.77 11.36 3 8.909.93 4 12.90 6.86 5 15.95 5.55 6 16.26 5.45 7 17.00 5.21 8 17.43 5.08 918.09 4.90 10 18.77 4.72 11 19.23 4.61 12 19.84 4.47 13 20.33 4.36 1420.63 4.30 15 22.56 3.94 16 23.16 3.84 17 24.32 3.66 18 24.83 3.58 1926.04 3.42 20 27.40 3.25 21 28.37 3.14 22 29.14 3.06 23 30.17 2.96 2431.20 2.86 25 32.52 2.75 26 33.68 2.66 27 34.35 2.61 28 36.37 2.47 2937.85 2.38 30 38.91 2.31

First Preparation of Crystalline ELQ-300-Form II and Characterization

All operations were carried out at room temperature, at 18-23° C. unlessspecifically stated. 37 mg of ELQ-300-Form IA was completely dissolvedin 5 mL of DCM-MeOH mixture (1:1). The solution was stirred at 200 rpmand 15 mL of hexane was added to the solution over about 0.5 min.Precipitates were observed after addition of hexane and the suspensionwas kept stirring at 200 rpm for 3 hours. The sample was centrifuged at14,000 rpm for 10 min and the precipitates were dried overnight in avacuum oven at 40° C. Obtained product was characterized by XRPD and DSCand shown to be a new crystalline form, which was designatedELQ-300-Form II. FIG. 7 shows the characteristic X-ray diffractionpattern of the crystalline ELQ-300-Form II. Characteristic reflectionsand the corresponding d-spacings for crystalline Form II are shown inTable 6. FIG. 8 shows the DSC of the crystalline ELQ-300-Form II.

TABLE 6 No. 2-Theta (°) d-spacing (Å) 1 4.37 20.19 2 5.12 17.24 3 7.6711.52 4 8.94 9.89 5 10.23 8.64 6 12.74 6.94 7 15.29 5.79 8 15.76 5.62 917.30 5.12 10 17.85 4.97 11 18.63 4.76 12 19.11 4.64 13 20.14 4.41 1420.43 4.34 15 20.94 4.24 16 22.43 3.96 17 23.01 3.86 18 24.18 3.68 1925.62 3.47 20 28.20 3.16 21 30.88 2.89 22 31.54 2.83 23 32.28 2.77 2432.62 2.74 25 33.50 2.67 26 36.11 2.49 27 38.79 2.32

1^(st) Scale Up of Crystalline ELQ-300-Form II and Characterization

All operations were carried out at room temperature, at 18-23° C. unlessspecifically stated. 188.64 mg of ELQ-300-Form IA was completelydissolved in 15 mL of DCM-MeOH mixture (1:1). The solution was stirredat 200 rpm and 45 mL of hexane was added to the solution over about 1min. Precipitates were observed after addition of hexane and thesuspension was kept stirring at 200 rpm for 3 hours. The sample wascentrifuged at 14,000 rpm for 10 min and the precipitates were driedovernight in a vacuum oven at 40° C. Obtained product was characterizedby XRPD to confirm the formation of crystalline Form II and named as 1stscale up batch of crystalline ELQ-300-Form II. FIG. 9 shows thecharacteristic X-ray diffraction pattern of the scaled up crystallineELQ-300-Form II (1^(st) scale up batch). Characteristic reflections andthe corresponding d-spacings for the scaled up crystalline ELQ-300-FormII (1st scale up batch) are shown in Table 7.

TABLE 7 No. 2-Theta (°) d-spacing (Å) 1 5.11 17.29 2 7.65 11.55 3 8.959.87 4 10.21 8.66 5 12.74 6.94 6 15.28 5.79 7 15.70 5.64 8 17.30 5.12 917.85 4.97 10 18.56 4.78 11 19.05 4.66 12 19.68 4.51 13 19.68 4.51 1420.12 4.41 15 20.43 4.34 16 22.48 3.95 17 23.03 3.86 18 24.19 3.68 1925.60 3.48 20 27.93 3.19 21 28.22 3.16 22 29.92 2.98 23 30.82 2.90 2432.18 2.78 25 32.36 2.76 26 32.54 2.75 27 33.47 2.68 28 36.11 2.49 2938.81 2.32

2^(nd) Scale Up of Crystalline ELO-300-Form II and Characterization

All operations were carried out at room temperature, at 18-23° C. unlessspecifically stated. 1.2 grams of ELQ-300-Form IB was completelydissolved in 100 mL of DCM-MeOH mixture (1:1). The solution was stirredat 200 rpm and 290 mL of hexane was added to the solution over about 3min. Precipitates were observed after addition of hexane and thesuspension was kept stirring at 200 rpm for 2 days. The sample wascentrifuged at 14,000 rpm for 10 min and the precipitates were driedovernight in a vacuum oven at 40° C. Obtained product was characterizedby XRPD and DSC to confirm the formation of crystalline Form II andnamed as 2^(nd) scale up batch of crystalline ELQ-300-Form II. FIG. 10shows the characteristic X-ray diffraction pattern of the 2^(nd) scaleup batch of crystalline ELQ-300-Form II. Characteristic reflections andthe corresponding d-spacings for the 2^(nd) scale up batch ofcrystalline Form II are shown in Table 8. FIG. 11 shows the DSC of the2^(nd) scale up batch of crystalline ELQ-300-Form II (2^(nd) scale upbatch).

TABLE 8 No. 2-Theta (°) d-spacing (Å) 1 5.16 17.10 2 7.69 11.48 3 8.999.83 4 10.21 8.66 5 12.22 7.24 6 12.75 6.94 7 15.28 5.79 8 15.77 5.62 916.40 5.40 10 17.33 5.11 11 17.90 4.95 12 18.65 4.75 13 19.07 4.65 1419.66 4.51 15 20.14 4.41 16 20.41 4.35 17 20.98 4.23 18 22.43 3.96 1922.98 3.87 20 23.76 3.74 21 24.22 3.67 22 24.71 3.60 23 25.61 3.48 2425.88 3.44 25 27.22 3.27 26 27.96 3.19 27 28.21 3.16 28 30.01 2.98 2930.74 2.91 30 32.28 2.77 31 32.52 2.75 32 33.43 2.68 33 34.19 2.62 3434.49 2.60 35 36.13 2.48 36 37.86 2.37 37 38.83 2.32

Crystalline ELQ-300-Form III and ELQ-300-Form IV

Crystalline ELQ-300-Form III was prepared by slurry method using THF asthe solvent and it was shown to be a solvate by DSC. After heating at100° C. for 5 min, the crystalline ELQ-300-Form III transferred to a newcrystalline form, which was designated crystalline ELQ-300-Form IV.

Preparation and Characterization of Crystalline ELO-300-Form III

About 30 mg of crystalline ELQ-300-Form IA was suspended in 0.3 mL ofTHF in an 1.5 mL sealed glass vial. The vial was placed in an EppendorfThermomixer and shaked at 50° C., 700 rpm for 72 h. The vial wascentrifuged to collect solids. XRPD showed that the isolated solids havea new XRPD pattern. Thus, the wet solids were dried overnight in avacuum oven at 40° C. and the resulting dried product was characterizedby XRPD and DSC to confirm the formation of a new crystalline Form,which was designated as ELQ-300-Form III. FIG. 12 shows thecharacteristic X-ray diffraction pattern of the crystalline ELQ-300-FormIII. Characteristic reflections and the corresponding d-spacings forcrystalline ELQ-300-Form III are shown in Table 9. DSC and TGA ofcrystalline ELQ-300-Form III are shown in FIG. 13A and FIG. 13Brespectively.

TABLE 9 No. 2-Theta (°) d-spacing (Å) 1 5.09 17.34 2 7.65 11.55 3 11.457.72 4 12.74 6.94 5 15.31 5.78 6 15.72 5.63 7 15.98 5.54 8 16.33 5.42 916.97 5.22 10 17.30 5.12 11 17.85 4.96 12 18.58 4.77 13 19.03 4.66 1419.62 4.52 15 20.10 4.41 16 20.43 4.34 17 20.91 4.25 18 22.38 3.97 1923.00 3.86 20 23.65 3.76 21 24.16 3.68 22 24.62 3.61 23 25.10 3.55 2425.60 3.48 25 25.81 3.45 26 27.18 3.28 27 27.86 3.20 28 28.20 3.16 2929.05 3.07 30 29.25 3.05 31 29.76 3.00 32 32.28 2.77 33 32.62 2.74 3433.09 2.71 35 33.49 2.67 36 33.68 2.66 37 34.20 2.62 38 34.51 2.60 3935.58 2.52 40 36.12 2.49 41 36.62 2.45 42 37.14 2.42 43 37.66 2.39 4438.79 2.32

Preparation and Characterization of Crystalline ELO-300-Form IV

The crystalline ELQ-300-Form III obtained from slurry in THF was heatedto 100° C. and maintained the temperature for 5 min, the obtainedproduct was characterized by XRPD, DSC and TGA and shown to be a newcrystalline Form, which was designated crystalline ELQ-300-Form IV. FIG.14 shows the characteristic X-ray diffraction pattern of the crystallineELQ-300-Form IV. Characteristic reflections and the correspondingd-spacings for crystalline ELQ-300-Form IV are shown in Table 10. DSCand TGA of crystalline ELQ-300-Form IV are shown in FIG. 15A and FIG.15B respectively.

TABLE 10 No. 2-Theta (°) d-spacing (Å) 1 7.65 11.55 2 8.91 9.92 3 12.976.82 4 15.88 5.58 5 17.45 5.08 6 18.04 4.91 7 18.81 4.71 8 19.19 4.62 919.77 4.49 10 20.29 4.37 11 20.64 4.30 12 21.08 4.21 13 22.48 3.95 1423.17 3.84 15 24.33 3.66 16 24.83 3.58 17 25.95 3.43 18 27.32 3.26 1928.32 3.15 20 29.92 2.98 21 30.07 2.97 22 32.46 2.76 23 32.72 2.74 2433.70 2.66 25 36.23 2.48 26 36.41 2.47

Preparation and Characterization of Crystalline ELO-300-Form V

Crystalline Form V was prepared by slurry method using NMP as thesolvent. About 48 mg of crystalline ELQ-300-Form IA was suspended in 0.2mL of NMP in an 1.5 mL sealed glass vial. The vial was placed in anEppendorf Thermomixer and shaked at 37° C., 700 rpm for 24 h. The vialwas centrifuged to collect the solids. XRPD showed that the isolatedsolids have a new XRPD pattern. Thus, 0.5 mL of ethanol was added to thewet solids for removing NMP. The sample was centrifuged at 14,000 rpmfor 10 min and the supernatant was removed. The precipitated solids weredried overnight in a vacuum oven at 30° C. and analyzed by XRPD, DSC andTGA. The obtained product was shown to be a new crystalline Form, whichwas designated ELQ-300-Form V.

FIG. 16 shows the characteristic X-ray diffraction pattern of thecrystalline ELQ-300-Form V. Characteristic reflections and thecorresponding d-spacings for crystalline Form V are shown in Table 11.DSC and TGA of crystalline ELQ-300-Form V are shown in FIG. 17A and FIG.17B respectively.

TABLE 11 No. 2-Theta (°) d-spacing (Å) 1 7.61 11.60 2 12.72 6.96 3 15.285.79 4 15.79 5.61 5 16.09 5.51 6 16.40 5.40 7 16.88 5.25 8 17.37 5.10 917.92 4.94 10 18.66 4.75 11 19.09 4.65 12 19.68 4.51 13 20.14 4.41 1420.41 4.35 15 20.98 4.23 16 22.44 3.96 17 23.01 3.86 18 23.71 3.75 1924.22 3.67 20 24.69 3.60 21 25.60 3.48 22 25.89 3.44 23 27.26 3.27 2427.95 3.19 25 28.20 3.16 26 28.87 3.09 27 29.11 3.07 28 30.01 2.98 2930.29 2.95 30 30.84 2.90 31 31.79 2.81 32 32.26 2.77 33 32.56 2.75 3433.48 2.67 35 33.68 2.66 36 34.22 2.62 37 34.44 2.60 38 34.93 2.57 3936.09 2.49 40 37.77 2.38 41 38.77 2.32

Example 8: Preparation and Characterization of ELO-300 Crystalline FormSuspension

Wet-milling method was used to prepare the suspensions. CrystallineELQ-300-Form II was selected as the raw material for milling andsuspensions in two formulations were prepared:

-   -   (a) 1% (w/v) Synperonic® F108 (Flake)—0.2% (w/v) dodecyl sodium        sulfate (SLS, Richjoint Chemicals); and    -   (b) 3% (w/v) D-α-tocopheryl polyethylene glycol 1000 succinate        (TPGS, Sigma Aldrich).

ELQ-300-Form II suspensions were prepared at two concentrations, 15mg/mL and 100 mg/mL, respectively.

Preparation of 15 mg/mL ELO-300-Form II Suspension

The 1^(st) scale up batch of crystalline ELQ-300-Form II was used toprepare 15 mg/mL ELQ-300-Form II suspensions. About 30 mg of theobtained crystalline ELQ-300-Form II was weighted in a 30 mLhigh-density polyethylene bottle. 1.2 mL of suspension vehicle, i.e., 1%(w/v) Synperonic® F108-0.2% (w/v) SLS or 3% (w/v) TPGS, was added. 2.4mL of zirconium beads with a diameter of 0.8 mm (YTZ® Grinding Media,Nikkato Co., Japan) were added using a measuring cylinder. The bottleswere placed on a US Stoneware Roller Mixer and the rolling speed was setat 220 rpm.

The milling duration was 2 days and one drop of milled suspension wasdiluted with deionized water to for size distribution measurement byNicomp Zeta Potential & Particle Sizer 380. The suspensions were alsoexamined under PLM to see if the obtained products contained particlesbigger than 5 μm. If a majority of the particles were smaller than 5 μm,the suspensions were collected using a 1 mL pipette. Concentrations ofELQ-300-Form II in the suspensions were determination by HPLC. Thesuspensions were further diluted with their corresponding formulationvehicles to a final concentration of 15 mg/mL and stored in sealed glassvials at room temperature before PK study. Visual inspection of thesuspensions showed that the products were homogeneous, syringeable andeasily resuspendable following short-time vortex or water-bathsonication, suitable for preclinical PK study via intramuscularinjection. The suspensions were characterized on dosing day by particlesizer and HPLC to ensure that the samples remained stable after storageat room temperature in terms of particle size and API concentration.

Preparation of 100 mg/mL ELO-300-Form II Suspension

The 2^(nd) scaled up batch of crystalline ELQ-300-Form II was used forpreparing aqueous ELQ-300-Form II suspension at 100 mg/mL. Initially,the targeted concentration of ELQ-300-Form II suspensions was set at 200mg/mL. About 250 mg of the crystalline ELQ-300-Form II was weighted in a30 mL high-density polyethylene bottle. 1 mL of suspension vehicle,i.e., 1% (w/v) Synperonic® F108—0.2% (w/v) SLS or 3% (w/v) TPGS, wasadded. 2 mL of zirconium beads with a diameter of 0.8 mm (YTZ® GrindingMedia, Nikkato Co., Japan) were added using a measuring cylinder. Thebottles were placed on a US Stoneware Roller Mixer and the rolling speedwas set at 220 rpm. After 2 days of milling, the crystals suspended inboth milling vehicles formed a solid paste. Thus, extra milling medium(approximately 1 mL) was added to each sample for getting a liquid formfor continued milling. The samples were milled for 72 h and the productswere characterized by Nicomp Zeta Potential & Particle Sizer 380, PLMand HPLC as described above. The suspensions were further diluted withtheir corresponding formulation vehicles to a final concentration of 100mg/mL for PK study. Visual inspection of the suspensions showed that theproducts were homogeneous, syringeable and easily resuspendablefollowing short-time vortex or water-bath sonication, suitable forpreclinical PK study via intramuscular injection. The suspensions werecharacterized on dosing day by particle sizer and HPLC to ensure thatthe samples remained stable after storage at room temperature in termsof particle size and API concentration.

Example 9: Synthesis of Atovaquone Crystalline Forms

Polymorph screening of atovaquone identified two stable forms. The rawform is characterized by large crystals of varying shape with lengths aslarge as 5 mm (atovaquone-form I). A second polymorph was identified byevaporation of the raw API from acetone: 1,4-dioxane (1:1). Thiscrystalline form, named atovaquone-form II, was characterized by PLM andfound to be small needles.

Characterization of the Crystalline Atovaquone-Form I

The crystalline atovaquone-Form I was characterized by XRPD and DSC.FIG. 23 shows the characteristic X-ray diffraction pattern of thecrystalline atovaquone-Form I. Characteristic reflections and thecorresponding d-spacings for crystalline atovaquone-Form I are shown inTable 12. FIG. 24A shows DSC of the crystalline atovaquone-Form I. FIG.24B shows TGA of the crystalline atovaquone-Form I.

TABLE 12 No. 2-Theta (°) d-spacing (Å) 1 7.26 12.17 2 7.44 11.87 3 9.888.95 4 10.90 8.11 5 11.21 7.89 6 11.92 7.42 7 14.66 6.04 8 15.61 5.67 916.29 5.44 10 16.94 5.23 11 17.54 5.05 12 18.11 4.90 13 19.43 4.57 1420.12 4.41 15 21.42 4.14 16 22.25 3.99 17 22.98 3.87 18 23.73 3.75 1924.86 3.58 20 25.07 3.55 21 25.31 3.52 22 26.36 3.38 23 26.79 3.33 2427.66 3.22 25 28.59 3.12 26 28.81 3.10 27 29.30 3.05 28 29.87 2.99 2930.14 2.96 30 30.84 2.90 31 32.23 2.78 32 32.91 2.72 33 33.63 2.66 3434.36 2.61 35 35.56 2.52 36 36.02 2.49 37 36.69 2.45 38 38.21 2.35 3939.63 2.27

Preparation and Characterization of the Crystalline Atovaquone-Form II

Crystalline atovaquone-Form II was prepared by solvent evaporationmethod. All operations were carried out at room temperature, at 18-23°C. unless specifically stated. 300 mg of atovaquone-Form I was weightedin a 40 mL glass vial and 9 mL of a mixture of acetone and 1,4-dioxane(volume ratio: 1:1) was added. Short time of vortex or sonication(around 5 to 10 s) was also used and atovaquone-Form I completelydissolved easily. The vial was covered with a piece of aluminium foilwith pinholes for overnight solvent evaporation in a fume cupboard atroom temperature. The obtained solids were further dried overnight in avacuum oven at 30° C. and then characterized by XRPD, DSC and TGA. Theproduct was shown to be a new crystalline Form, which was designatedcrystalline atovaquone-Form II. FIG. 25 shows the characteristic X-raydiffraction pattern of the crystalline atovaquone-Form II.Characteristic reflections and the corresponding d-spacings forcrystalline atovaquone-Form II are shown in Table 13. FIG. 26A shows theDSC of the crystalline atovaquone-Form II. FIG. 26B shows the DSC of thecrystalline atovaquone-Form II.

TABLE 13 No. 2-Theta (°) d-spacing (Å) 1 7.02 12.57 2 9.29 9.51 3 9.719.10 4 12.77 6.93 5 14.29 6.19 6 14.86 5.96 7 15.25 5.80 8 17.14 5.17 918.62 4.76 10 19.29 4.60 11 20.13 4.41 12 20.53 4.32 13 20.73 4.28 1421.92 4.05 15 22.17 4.01 16 22.78 3.90 17 23.36 3.81 18 24.38 3.65 1925.35 3.51 20 25.66 3.47 21 26.38 3.38 22 26.97 3.30 23 27.29 3.27 2427.78 3.21 25 28.59 3.12 26 28.88 3.09 27 30.66 2.91 28 32.77 2.73 2933.60 2.67 30 35.27 2.54 31 37.72 2.38 32 38.04 2.36 33 38.46 2.34 3438.72 2.32 35 39.66 2.27

Example 10: Preparation and Characterization of Atovaquone CrystallineForm Suspension

Wet-milling method was used to prepare crystalline atovaquonesuspensions. Both crystalline atovaquone-Form I and atovaquone-Form IIwere used as the raw material for milling and suspensions using 1% (w/v)Synperonic® F108 (Flake)—0.2% (w/v) dodecyl sodium sulfate (SLS,Richjoint Chemicals), targeted concentration of 200 mg/mL. However,crystalline atovaquone-Form I was not suitable for the suspensionpreparation, as big rod-shaped crystals around 5 mm in length wereobserved in collected suspension, which may be explained by the Ostwaldripening theory. In contrast, a nanosuspension of crystalline atovaquoneForm II at 200 mg/mL was successfully prepared and used in the PKstudies.

Preparation of 200 mg/mL Nanosuspensions Using CrystallineAtovaquone-Form II

Crystalline atovaquone-Form II was used to prepare 200 mg/mLnanosuspension. About 200 mg of the obtained crystalline atovaquone-FormII was weighted in a 30 mL high-density polyethylene bottle. 0.8 mL ofsuspension vehicle, i.e., 1% (w/v) Synperonic® F108—0.2% (w/v) SLS, wasadded. 1.6 mL of zirconium beads with a diameter of 0.8 mm (YTZ®Grinding Media, Nikkato Co., Japan) were added using a measuringcylinder. The bottles were placed on a US Stoneware Roller Mixer and therolling speed was set at 220 rpm. The milling duration was 3 days andone drop of milled suspension was diluted with deionized water for sizedistribution measurement by Nicomp Zeta Potential & Particle Sizer 380.The suspension was also examined under PLM to see if the obtainedproduct contained particles bigger than 5 μm. If a majority of theparticles were smaller than 5 min, the suspension was collected using an1 mL pipette. Concentration of atovaquone-Form II in the suspension wasdetermined by HPLC. The suspension was further diluted with 1% (w/v)Synperonic® F108—0.2% (w/v) SLS to a final concentration of 200 mg/mL.The final product was stored in an 1.5 mL sealed glass vial at roomtemperature and protected from light before PK study. Visual inspectionof the suspensions showed that the products were homogeneous,syringeable and easily resuspendable following short-time vortex orwater-bath sonication, suitable for preclinical PK study viaintramuscular injection. The suspensions were characterized on dosingday by particle sizer and HPLC to ensure that the samples remainedstable after storage at room temperature in terms of particle size andAPI concentration.

Example 11: Synthesis of Pyronaridine Crystalline Forms

Four new crystalline forms of pyronaridine are summarized in Table 14and designated as Form II, Form III. Form IV and Form V.

TABLE 14 Crystalline Preparation Form No. method Solvent used andconditions Form II Slurry method EtOH 40° C., 48 hr Form III Slurrymethod IPA 40° C., 48 hr acetone THF 1,4-Dioxane Form IV Slurry methodMeOH:H2O (v:v, 3:1) 40° C., 48 hr EtOH:H2O (v:v, 3:1) Acetone:H2O (v:v,1:2) IPA:H2O (v:v, 1:1) Form V Heating method No solvents used, heatedto 120° C. for 5 min

Characterization of the Crystalline Pyronaridine-Form I

Crystalline pyronaridine-Form I was characterized by XRPD, DSC and TGA.FIG. 28 shows the characteristic X-ray diffraction pattern of thecrystalline pyronaridine-Form I. Characteristic reflections and thecorresponding d-spacings for crystalline pyronaridine-Form I are shownin Table 15. FIG. 29A shows DSC of the crystalline pyronaridine-Form I.FIG. 29B shows TGA of the crystalline pyronaridine-Form I.

TABLE 15 No. 2-Theta (°) d-spacing (Å) 1 7.44 11.88 2 9.65 9.16 3 11.297.83 4 12.65 6.99 5 13.41 6.60 6 14.19 6.24 7 14.74 6.00 8 15.51 5.71 915.85 5.59 10 16.38 5.41 11 16.72 5.30 12 17.23 5.14 13 17.88 4.96 1418.18 4.88 15 18.60 4.77 16 20.06 4.42 17 20.51 4.33 18 21.12 4.20 1921.89 4.06 20 22.58 3.93 21 23.56 3.77 22 23.83 3.73 23 24.30 3.66 2425.57 3.48 25 25.86 3.44 26 26.22 3.40 27 26.75 3.33 28 27.13 3.28 2928.47 3.13 30 28.96 3.08 31 30.03 2.97 32 31.89 2.80 33 32.65 2.74 3436.31 2.47

Preparation of Crystalline Pyronaridine-Form II, Pyronaridine-Form IIIand Pyronaridine-Form IV and Characterization Results

Crystalline Form II, Form III and Form IV of pyronaridine were preparedby slurry method using different solvents (details summarized in Table14). About 30 mg of crystalline pyronaridine-Form I was suspended in 0.2mL of each solvent in a 1.5 mL sealed glass vial. The vial was placed inan Eppendorf Thermomixer and shaken at 40° C., 700 rpm for 48 h. The APIsolids were collected by centrifugation and shown to be new crystallineforms. Thus, the wet solids were dried overnight in a vacuum oven at 30°C. and the resulting dried products were characterized by XRPD, DSC andTGA.

The new crystalline form obtained from slurry in ethanol was designatedpyronaridine-Form II. FIG. 30 shows the characteristic X-ray diffractionpattern of the crystalline pyronaridine-Form II. Characteristicreflections and the corresponding d-spacings for crystallinepyronaridine-Form II are shown in Table 16. FIG. 31A shows the DSC ofthe crystalline pyronaridine-Form II. FIG. 31B shows the TGA of thecrystalline pyronaridine-Form II.

TABLE 16 No. 2-Theta (°) d-spacing (Å) 1 6.76 13.06 2 7.40 11.94 3 8.4510.46 4 9.08 9.73 5 10.62 8.33 6 12.93 6.84 7 13.48 6.56 8 14.84 5.96 915.23 5.81 10 15.67 5.65 11 16.68 5.31 12 16.92 5.24 13 17.43 5.08 1418.20 4.87 15 18.57 4.77 16 18.91 4.69 17 19.90 4.46 18 20.49 4.33 1920.93 4.24 20 21.08 4.21 21 21.97 4.04 22 22.27 3.99 23 22.46 3.95 2423.65 3.76 25 24.32 3.66 26 24.56 3.62 27 25.94 3.43 28 27.17 3.28 2929.61 3.01 30 30.19 2.96 31 30.52 2.93 32 31.59 2.83 33 32.20 2.78 3432.76 2.73 35 33.31 2.69 36 33.92 2.64 37 34.69 2.58 38 35.70 2.51 3936.71 2.45 40 37.18 2.42 41 37.60 2.39 42 39.08 2.30

After slurry in IPA, acetone, THF and 1,4-Dioxane, the crystallinepyronaridine-Form I transferred to another new crystalline form, whichwas designated pyronaridine-Form III. FIG. 32 shows the characteristicX-ray diffraction pattern of the crystalline pyronaridine-Form III.Characteristic reflections and the corresponding d-spacings forcrystalline Form III are shown in Table 17. FIG. 33A shows the DSC ofthe crystalline pyronaridine-Form III. FIG. 33B shows the TGA of thecrystalline pyronaridine-Form III.

TABLE 17 No. 2-Theta (°) d-spacing (Å) 1 5.68 15.55 2 6.71 13.17 3 7.9111.16 4 9.37 9.43 5 9.98 8.86 6 11.05 8.00 7 12.04 7.35 8 13.46 6.57 914.49 6.11 10 15.77 5.61 11 16.17 5.48 12 17.13 5.17 13 17.98 4.93 1418.84 4.71 15 19.03 4.66 16 19.44 4.56 17 20.10 4.41 18 20.77 4.27 1921.46 4.14 20 21.65 4.10 21 22.38 3.97 22 22.94 3.87 23 23.17 3.84 2423.83 3.73 25 24.50 3.63 26 24.80 3.59 27 25.08 3.55 28 25.63 3.47 2926.31 3.38 30 26.50 3.36 31 27.05 3.29 32 28.02 3.18 33 28.36 3.14 3429.23 3.05 35 29.60 3.02 36 29.79 3.00 37 30.51 2.93 38 30.76 2.90 3931.62 2.83 40 31.89 2.80 41 32.25 2.77 42 32.93 2.72 43 33.75 2.65 4434.69 2.58 45 36.57 2.46 46 37.49 2.40 47 38.37 2.34 48 38.97 2.31

The dried crystals obtained after slurry in MeOH:H₂O (v:v, 3:1),EtOH:H₂O (v:v, 3:1), acetone:H₂O (v:v, 1:2) and IPA:H₂O (v:v, 1:1)showed a different crystalline form from Form I, II and III ofpyronaridine and it was designated crystalline pyronaridine-Form IV.FIG. 34 shows the characteristic X-ray diffraction pattern of thecrystalline pyronaridine-Form IV. Characteristic reflections and thecorresponding d-spacings for crystalline Form IV are shown in Table 18.FIG. 35A shows the DSC of the crystalline pyronaridine-Form IV. FIG. 35Bshows the TGA of the crystalline pyronaridine-Form IV.

TABLE 18 No. 2-Theta (°) d-spacing (Å) 1 8.36 10.57 2 9.35 9.45 3 10.938.09 4 14.27 6.20 5 14.55 6.08 6 15.46 5.73 7 16.48 5.38 8 17.84 4.97 918.04 4.91 10 18.40 4.82 11 19.03 4.66 12 19.45 4.56 13 20.37 4.36 1420.65 4.30 15 21.32 4.16 16 21.97 4.04 17 22.80 3.90 18 23.41 3.80 1924.58 3.62 20 24.91 3.57 21 25.33 3.51 22 25.88 3.44 23 27.54 3.24 2428.01 3.18 25 28.35 3.15 26 28.86 3.09 27 29.26 3.05 28 29.93 2.98 2931.57 2.83 30 32.73 2.73 31 33.43 2.68

Preparation of Crystalline Pyronaridine-Form V and CharacterizationResults

Crystalline pyronaridine-Form V was prepared from crystallinepyronaridine-Form I by heating and cooling method. About 10 mg ofcrystalline pyronaridine-Form I was placed in an open platinum pan andheated by TA Q5000 TGA. The heating process was set to heat the samplefrom 25° C. to 120° C. at a rate of 10° C./min and maintained 120° C.for 5 min. After this, the powder was allowed to cool down to roomtemperature. The obtained solids were characterized by XRPD and DSC andshowed to be a new crystalline form, which was designated crystallinepyronaridine-Form V. FIG. 36 shows the characteristic X-ray diffractionpattern of the crystalline pyronaridine-Form V. Characteristicreflections and the corresponding d-spacings for crystallinepyronaridine-Form V are shown in Table 19. FIG. 37 shows the DSC of thecrystalline pyronaridine-Form V.

TABLE 19 No. 2-Theta (°) d-spacing (Å) 1 6.77 13.05 2 9.36 9.44 3 9.938.90 4 11.01 8.03 5 12.11 7.30 6 13.46 6.57 7 13.85 6.39 8 14.07 6.29 914.61 6.06 10 15.34 5.77 11 16.15 5.48 12 16.36 5.41 13 16.74 5.29 1417.31 5.12 15 17.57 5.04 16 17.87 4.96 17 18.35 4.83 18 19.07 4.65 1919.44 4.56 20 19.80 4.48 21 20.33 4.36 22 20.69 4.29 23 21.01 4.22 2422.95 3.87 25 23.48 3.79 26 24.20 3.67 27 24.87 3.58 28 25.49 3.49 2926.04 3.42 30 26.59 3.35 31 27.03 3.30 32 29.64 3.01 33 29.89 2.99 3432.56 2.75 35 32.59 2.75

Example 12: Pharmacokinetic Studies PO 1. Animals

Animals (Male CD-1 mice, 7-9 weeks) were obtained from an approvedvendor (SLAC Laboratory Animal Co. Ltd., Shanghai, China; or SIPPR-B&KLaboratory Animal Co. Ltd., Shanghai, China).

Acclimation/Quarantine:

Following arrival animals were assessed as to their general health by amember of the veterinary staff or other authorized personnel. Animalswere acclimated for at least 3 days before being placed on study.

Animal Husbandry:

Animals were group housed during acclimation and individually housedduring the study. The animal room environment was controlled (targetconditions: temperature 18 to 26° C., relative humidity 30 to 70%, 12hours artificial light and 12 hours dark). Temperature and relativehumidity was monitored daily.

Animals were fasted at least 12 hours prior to the administration. Allanimals had access to Certified Rodent Diet (Catalog # M01-F, SLACLaboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours postdosing.

Water was autoclaved before provided to the animals ad libitum. Periodicanalyses of the water was performed.

2. Formulation PO Formulation

Appropriate amount of test compound was accurately weighed and mixedwith appropriate volume of vehicle to get a clear solution or a uniformsuspension, vortexing or sonication in water bath was sometimes needed.The formulations were prepared on the day of dosing. Animals were dosedwithin four hours after the formulation was prepared. Two 20 μL aliquotsof each formulation were removed from each of the formulation solutions,transferred into 1.5 mL of polypropylene microcentrifuge tubes and rundose validation by LC/UV or LC-MS/MS.

3. Dose Administration

The PO dose formulation was administered via oral gavage followingfacility SOPs.

4. Sample Collection

For PO group, Approximately 30 μL blood was collected from saphenousvein at each time point. All blood samples were transferred intomicrocentrifuge tubes containing 2 μL of K₂EDTA (0.5M) as anti-coagulantand placed on wet ice until processed for plasma.

5. Blood/Plasma Processing

Blood samples were processed for plasma by centrifugation atapproximately 4° C., 3000 g 15 min within half an hour of collection.Plasma samples were stored in polypropylene tubes, quick frozen over dryice and kept at −70±10° C. until LC/MS/MS analysis.

6. Sample Analysis Dose Formulation Concentration Verification

-   -   Aliquots of the formulations were collected in the middle        position of each dose formulation in duplicate.    -   The concentrations of the test compound in dose formulation        samples were determined by the LC/UV or LC/MS/MS method.

Bioanalytical Method and Sample Analysis

-   -   LC-MS/MS methods for the quantitative determination of test        compound in corresponding biological matrix was developed under        non-GLP compliance.    -   A calibration curve with 8 non-zero calibration standards was        applied for the method including LLOQ.    -   A set of QC samples consisting of low, middle, and high        concentration was applied for the method.    -   The study sample analysis was performed concurrently with a set        of calibration standards and two sets of QC samples using the        LC-MS/MS method (If sample numbers are more than 48, then two        calibration curves with 2 sets of QC samples will be applied).

Acceptance Criteria:

-   -   Linearity: a minimum of 6 calibration standards was back        calculated to within +20% of their nominal values in plasma    -   Accuracy: A minimum of 4 out of 6 QC samples was back calculated        to within +20% of their nominal values in plasma.    -   Specificity: The mean calculated concentration in the single        blank matrix should be 0.5 times the LLOQ.    -   Sensitivity: LLOQ target: 1˜3 ng/mL.    -   Carryover: the mean calculated carry-over concentration in the        single blank matrix immediately after the highest standard        injection should be ≤LLOQ. If the carryover couldn't meet the        criteria, then the percent of carryover should be estimated        following in-house bioanalytical SOP.

7. Data Analysis

Plasma concentration versus time data was analyzed by non-compartmentalapproaches using the Phoenix WinNonlin 6.3 software program. C_(max),T_(max), T_(1/2), AUC_((0-t)), AUC_((0-inf)), MRT_((0-t)),MRT_((0-inf)), % F and graphs of plasma concentration versus timeprofile will be reported.

IM/SC 1. Animal

Rats (Sprague-Dawley, Male, 7-9 weeks) were obtained from an approvedvendor (SLAC Laboratory Animal Co. Ltd., Shanghai, China or SIPPR/BKLaboratory Animal Co. Ltd., Shanghai, China

Acclimation/Quarantine:

Following arrival animals were assessed as to their general health by amember of the veterinary staff or other authorized personnel. Animalswere acclimated for at least 3 days before being placed on study.

Animal Husbandry:

Animals were group housed during acclimation and individually housedduring the study. The animal room environment was controlled (targetconditions: temperature 18 to 26° C., relative humidity 30 to 70%, 12hours artificial light and 12 hours dark). Temperature and relativehumidity was monitored daily.

Animals were fasted at least 12 hours prior to the administration. Allanimals had access to Certified Rodent Diet (Catalog # M01-F, SLACLaboratory Animal Cl. Ltd., Shanghai, China) ad libitum 4 hours postdosing. Water was autoclaved before provided to the animals ad libitum.Periodic analyses of the water was performed.

2. Dose Formulation

Formulation will be picked up directly from PDS.

Two 20 μL aliquots of each formulation will be removed from each of theformulation solutions, transferred into 1.5 mL of polypropylenemicrocentrifuge tubes and run dose validation by LC/UV or LC-MS/MS.

3. Dose Administration

For IM/SC dosing, the dose formulation were administered viaintramuscular/subcutaneous injection following facility SOPs.

4. Sample Collection

Approximately 200 μL blood were collected from saphenous vein at eachtime point. All blood samples were transferred into microcentrifugetubes containing 4 μL of K₂EDTA (0.5M) as anti-coagulant and placed onwet ice until processed for plasma.

5. Blood/Plasma Processing

Blood samples were processed for plasma by centrifugation atapproximately 4° C., 3000 g 15 min within half an hour of collection.Plasma samples will be stored in polypropylene tubes, quick frozen overdry ice and kept at −70±10° C. until LC/MS/MS analysis.

6. Sample Analysis Dose Formulation Concentration Verification

-   -   For the clear solution, 1 sample were collected in the middle of        each dose formulation; for the suspension, 3 samples were        collected from top, middle, button of each dose solution.    -   A LC/UV method was developed and 1 standard solution was        prepared.    -   The peak area of test article in dose formulation solution and        in standard solution samples was determined by the LC/UV method    -   Acceptance criteria: the peak area of formulation solution        sample was within 80%-120% of that in standard solution.

Bioanalytical Method and Sample Analysis

-   -   LC-MS/MS methods for the quantitative determination of test        compound in corresponding biological matrix was developed under        non-GLP compliance.    -   A calibration curve with 8 non-zero calibration standards was        applied for the method including LLOQ.    -   A set of QC samples consisting of low, middle, and high        concentration was applied for the method.    -   The study sample analysis was performed concurrently with a set        of calibration standards and two sets of QC samples using the        LC-MS/MS method (If sample numbers are more than 48, then two        calibration curves with 2 sets of QC samples will be applied).

Acceptance Criteria:

-   -   Linearity: a minimum of 6 calibration standards was back        calculated to within ±20% of their nominal values in plasma    -   Accuracy: A minimum of 4 out of 6 QC samples was back calculated        to within +20% of their nominal values in plasma.    -   Specificity: The mean calculated concentration in the single        blank matrix should be 0.5 times the LLOQ.    -   Sensitivity: LLOQ target: 1˜3 ng/mL.    -   Carryover: the mean calculated carry-over concentration in the        single blank matrix immediately after the highest standard        injection should be ≤␣LLOQ. If the carryover couldn't meet the        criteria, then the percent of carryover should be estimated        following in-house bioanalytical SOP.

7. Data Analysis

Plasma concentration versus time data will be analyzed bynon-compartmental approaches using the Phoenix WinNonlin 6.3 softwareprogram. C_(max), T_(max), T_(1/2), AUC_((0-t)), AUC_((0-inf)),MRT_((0-t)), MRT_((0-inf)), % F and graphs of plasma concentrationversus time profile will be reported.

Table 20 shows the PK data for Compound 2 following PO and IMadministration. Graph is shown in FIG. 1.

TABLE 20 Compound 2 (PO) Compound 2 (IM) mpk 0.03 0.1 0.3 0.03 0.1 0.3C_(max) (nM) 45.2 173.4 554.8 ND 5.6 18.7 T_(max) (h) 3.67 3.0 4.67 ND96 112 T_(1/2) (h) 24.9 23.7 22.5 ND — 418 AUC_(0-last) (nM · h) 14504936 16524 ND 797 2801 AUC_(0-inf) (nM · h) 1555 5044 16764 ND 2972 4823CL/F (mL/min/kg) 0.576 0.599 0.520 ND 0.586 0.864

Table 21 shows the average plasma concentration of ELQ-300 following IMadministration of Compound 2 at 3 doses (3, 10, and 30 mg/kg). Table 22shows the ELQ-300 plasma concentration in all animals at day 14 (priorto the sporozoites challenge). The exposure is not highly variablebetween animals in a given group. The C_(trough) is about 83±32 nM foranimals that are protected from infection. The graphs are shown in FIG.2A and FIG. 2B.

TABLE 21 ELQ-300 (nM) Time 3.33 mg/kg 10 mg/kg 30 mg/kg  1 d 723 ± 1442942 ± 633  10959 ± 2029  7 d 36 ± 16 112 ± 66  257 ± 70 14 d 27 ± 14 68± 40 214 ± 54 21 d 28 ± 17 88 ± 61 155 ± 38 28 d 21 ± 32 69 ± 37 181 ±59

TABLE 22 3 mg/kg 10 mg/kg 30 mg/kg 5 43 nM  9  56 nM 13 137 nM 6 15 nM10  73 nM 14 219 nM 7 35 nM 11 119 nM 15 246 nM 8 15 nM 12  23 nM 16 256nM

Table 23 shows rat PK data for compound 2 (3.72 mg/kg in 100% sesameoil) injected intramuscularly. Table 24 shows the average plasmaconcentration of ELQ-300 following IM administration of Compound 2. RatIM PK of Compound 2 demonstrated a slow release for the first month withELQ-300 plasma level around 70 nM week two through four an significantburst in day 1 and significant drop in concentration between week oneand two. The graph is shown in FIG. 3A.

TABLE 23 mpk 3.72 C_(max) (nM) 399.3 ± 340  T_(max) (h)  49.7 ± 38.7T_(1/2) (h)   359 ± 25.5 AUC_(0-last) (nM · h) 68060 ± 3966 AUC_(0-inf)(nM · h) 103311 ± 9144  CL/F (mL/min/kg)  1.05 ± 0.09

TABLE 24 Time ELQ-300 (nM)  1 h 151 ± 209  8 h 235 ± 281  1 d 151 ± 209 3 d 157 ± 80   6 d 169 ± 22  13 d 73 ± 17 20 d 75 ± 19 27 d 68 ± 5 

Table 24A shows dog PK data for crystalline compound 2 (20 mg/mL, 3%TPGS, 1% HPMC E5 suspension) injected intramuscularly. Compound 2 wasdosed in dog at 10 mg/kg (Injection volume: 0.5 mL/kg). The material wasformulated as a 20 mg/mL suspension in 3% TPGS and 1% HPMC E5. Compound2 plasma exposure was low but detectable throughout the duration of thestudy. Plasma concentrations of ELQ-300 remained several orders ofmagnitude higher than that of Compound 2. Half-life of ELQ-300 was abouttwice as long as that of compound 2 (205 and 124 respectively).Additionally, clearance of ELQ-300 remained very low (0.23 mL/min/kg).The graph is shown in FIG. 3B.

TABLE 24A Compound 2 ELQ-300 T_(max) (h) 3 (2) 48 (0) T_(1/2) (h) 124(34) 205 (39) C_(max) (nM) 730 (149) 4639 (832) C_(last) (mM) 4.5 (4.7)482 (123) AUC_(0-last) (nM · h) 16427 (3738) 1140080 (100116)AUC_(0-inf) (nM · h) 18054 (3387) 1287335 (95176) CL/F (mL/min/kg) 14.4(3.3) 0.23 (0.02)

Table 25 shows the ELQ-300 plasma concentration following administrationof compounds 2, 8, 9, 10, 12, 16, 17, and 18 (3 mg/kg, 1.5 mg/mL in 100%sesame oil). Graphs are shown in FIG. 4A and FIG. 4B.

TABLE 25 ELQ-300 (nM) Time 2 8 9 10 12 16 17 18 8 h 175 ± 82 27 ± 22 38± 6  12 ± 11 948 ± 609 272 ± 393 50 ± 3 17 ± 7   1 d 142 ± 42 23 ± 16 24± 4  15 ± 17 406 ± 165 137 ± 97  28 ± 5 10 ± 4   6 d  85 ± 40 31 ± 9  32± 15 34 ± 7  156 ± 45  18 ± 5  12 ± 3 3.0 ± 5   13 d 46 ± 8 28 ± 9  33 ±10 38 ± 2  83 ± 30 20 ± 20  5 ± 1 1.6 ± 1.4 27 d  27 ± 16 32 ± 11 36 ±7  33 ± 5   6 ± 3 2.5 ± 0.4

Table 26 shows the average plasma concentration of ELQ-300 following IMadministration of suspensions of ELQ-300-Form II in two differentformulations (15 mg/mL, 30 mg/kg) as compared to the average plasmaconcentration of ELQ-300 following IM administration of Compound 2 andCompound 13 in 100% sesame oil (1.5 mg/mL, 3 mg/kg). The graph is shownin FIG. 18.

TABLE 26 ELQ-300 (μM) 1% Synperonic ® F ELQ-300 (nM) Time 3% TPGS108-0.2% SLS Comp. 2 Comp. 13  8 h 1.7 ± 0.3 1.7 ± 0.1 175 ± 82  382 ±48  1 d 2.1 ± 0.4 2.5 ± 0.9 142 ± 42  410 ± 83  6 d 1.3 ± 0.2 2.4 ± 0.3123 ± 85  313 ± 89 13 d 0.8 ± 0.1 1.1 ± 0.2 46 ± 8  110 ± 7  20 d 0.64 ±0.99 0.94 ± 0.03 32 ± 16 79 ± 6 27 d 0.48 ± 0.04 0.78 ± 0.24 27 ± 16 80± 7

Table 27 shows the mouse PK data following IM administration of 6different ELQ-300-Form II suspensions (100 mg/mL). IM1=Synperonic® 4mg/kg, IM2=Synperonic® 12 mg/kg, IM3=Synperonic® 36 mg/kg. IM4=TPGS 4mg/kg, IM5=TPGS 12 mg/kg, IM6=TPGS 36 mg/kg. Dose proportionality (up to13 days) is observed in the 2 different vehicles. Graphs are shown inFIG. 19A and FIG. 19B.

TABLE 27 IM1 IM2 IM3 IM4 IM5 IM6 Nominal Dose 4 12 36 4 12 36 (mg/kg)Concentration 100 100 100 100 100 100 (mg/mL) Dose Volume (uL) 10 30 9010 30 90 t_(1/2) (h) 242 (34)  250 (36)  250 (38) 381 (182) 227 (41) 320 (83) C_(max) (nM) 333 (118) 820 (128) 1813 (255) 263 (17)  605 (342)855 (33) C_(last) (nM) 37 (2)  109 (25)  277 (13) 31 (4)  49 (4)  190(12) AUC (o-∞) 87091 235908 566904 70864 123766 342465 (nM · h/mL)(22497) (37505) (27951) (5521) (16564) (40399) CL/F (mL/h/kg) 1.7 (0.4)1.8 (0.3)  2.2 (0.1) 2.0 (0.2) 3.4 (0.5)  3.7 (0.4)

Table 28 shows the mouse PK data following IM administration of 2different ELQ-300-Form II suspensions (at 4 mg/kg) as compared with IMadministration of Compound 2 (at 4 mg/kg) in sesame oil. The graph isshown in FIG. 20.

TABLE 28 ELQ-300-Form II ELQ-300-Form II Compound 2 (Synperonic ®)(TPGS) (sesame oil) Nominal Dose 4 4 5 (mg/kg) Concentration 100 10012.5 (mg/mL) Dose Volume 10 10 100 (uL) t_(1/2) (h) 242 (34) 381 (182)359 (26) C_(max) (nM) 333 (118) 263 (17) 399 (54) C_(last) (nM) 37 (2)31 (4) 68 (4) AUC_(0-∞) 87091 (22497) 70864 (5521) 103321 (9160)(nM*h/mL) CL/F (mL/h/kg) 1.7 (0.4) 2.0 (0.2) 1.0 (0.1)

Table 29 shows the average atovaquone plasma concentration following IMand PO administration of Compound 27 (in sesame oil) as compared to POadministration of atovaquone. The graph is shown in FIG. 21.

TABLE 29 Atovaquone from Compound 27 (μM) Time IM PO  8 h 4.6 ± 2.7 19 ±3   1 d 4.9 ± 1.6 27 ± 9   7 d 3.8 ± 2.1 15 ± 11 14 d 2.8 ± 0.9 0.3 ±0.3 28 d 3.3 ± 0.9 BQL

Table 30 shows the average atovaquone plasma and liver concentrationfollowing IM administration of Compound 27 at three different doses(16.7, 50, and 150 mg/kg). Table 31 shows the plasma concentration byanimal in the 16.7 mg/kg group. Graphs are shown in FIG. 22A and—FIG.22B

TABLE 30 Atovaquone (nM) Time 16.7 mg/kg 50 mg/kg 150 mg/kg  1 d 1445 ±550  6371 ± 3619 8035 ± 3452 14 d 55 ± 25  295 ± 280 1279 ± 752  28 d 35± 31* 180 ± 68  1170 ± 644  49 d 33 ± 11* 75 ± 38 294 ± 85  49 d (liver)36.7 ± 0.2  138 ± 28  *For surviving animals

TABLE 31 Atovaquone (nM) Time Animal 5 Animal 6 Animal 7 Animal 8  1 d1761 660 1477 1884  7 d 78 148 152 102 14 d 30 61 88 40 21 d 47 49 78 5528 d — 19 56 65 49 d — — 40 25

Table 32 shows the average Atovaquone concentration following IM ratadministration of Compound 33 at two different doses (20 and 60 mg/kg)formulated in sesame oil. Table 33 shows the liver and brain exposuresat week 13. The Graph is shown in FIG. 38.

TABLE 32 Compound 33 Compound 33 Dose of ATO (mg/kg) 20 60 Concentrationof ATO 295 mg/mL 295 mg/mL (max concentration) (650 mg/mL) (650 mg/mL)Injection Volume (uL) 2 × 10 2 × 30 Formulation Sesame oil solutionSesame oil solution C_(max) (nM) 13813 (4909) 35349 (5413) C_(last) (nM)2256 (935) 5379 (886) AUC_(0-∞) (nM*h/mL) 8172753 (466892) 23869258(1387755) CL/F (mL/min/kg) 0.06 (0.02) 0.06 (0.03)

TABLE 33 Compound 33 Compound 33 Dose of ATO (mg/kg) 20 60 LiverExposure (nM) 2793 (944) 3717 (351) Brain Exposure (nM) 37.9 (13.8) 64.0(10.3)

Table 34 shows the average ELQ-300 concentration following IM ratadministration of Compound 35 at two different doses (10.5 and 30 mg/kg)formulated in sesame oil. The Graph is shown in FIG. 39.

TABLE 34 Compound 35 Compound 35 Dose of ELQ-300 (mg/kg) 10.5 30Concentration of ELQ-300 291 mg/mL 291 mg/mL (max concentration) (580mg/mL) (580 mg/mL) Injection Volume (uL) 10 30 C_(max) (nM) 2265 (512)2431 (1105) C_(last) (nM) 51 (10) 145 (11) AUC_(0-∞) (nM*h/mL) 410174(22195) 1024416 (225651 CL/F (mL/min/kg) 0.8 (0.1) 0.9 (0.2)

Table 35 shows the average ELQ-300 concentration following IM ratadministration of crystalline Compound 2 at two different doses (8 and24 mg/kg). Table 36 shows key in vitro ADME for Compound 2. The Graph isshown in FIG. 40.

TABLE 35 Compound 2 Compound 2 Dose of ELQ-300 (mg/kg) 8 24 Formulation34 mg/mL in 3% TPGS and 1% HPMC E5 Injection Volume (uL) 59 177 C_(max)(nM) 474 (70) 1201 (114) C_(last) (nM) 90 (10) 232 (28) AUC_(0-∞)(nM*h/mL) 108338 (5183) 332595 (47709) CL/F (mL/min/kg) 1.37 (0.22) 1.57(0.19)

TABLE 36 Plasma Liver S9 % remaining after 2 hours Hepatocyte T1/2 Mouse 0% Rat  0% Dog 83% 47% 22 min Monkey 85% Human 82% 35% 77 min

Example 13: Solid State Characterization of(6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yloxy)methylbutyrate (Compound 2)

FIG. 41 shows the characteristic X-ray diffraction pattern of theCompound 2. Characteristic reflections and the corresponding d-spacingsfor crystalline Compound 2 are shown in Table 37. FIG. 42A shows the DSCof the crystalline compound 2 and FIG. 42B shows the TGA of thecrystalline compound 2.

TABLE 37 No. 2-Theta (°) d-spacing (Å) Height I% 1 8.90 9.93 503 6.3 212.31 7.19 474 5.9 3 13.04 6.78 337 4.2 4 13.93 6.35 749 9.4 5 14.446.13 6919 86.5 6 14.96 5.92 540 6.8 7 15.15 5.84 3178 39.7 8 16.30 5.44251 3.1 9 16.50 5.37 745 9.3 10 16.89 5.25 317 4 11 17.03 5.20 224 2.812 17.68 5.01 2694 33.7 13 18.11 4.89 2475 30.9 14 18.54 4.78 295 3.7 1519.06 4.65 1048 13.1 16 20.30 4.37 973 12.2 17 20.52 4.33 383 4.8 1820.80 4.27 721 9 19 21.21 4.19 1018 12.7 20 21.66 4.10 1910 23.9 2121.94 4.05 946 11.8 22 22.32 3.98 2300 28.8 23 22.59 3.93 8000 100 2422.99 3.87 566 7.1 25 23.44 3.79 332 4.2 26 23.62 3.76 646 8.1 27 24.093.69 783 9.8 28 24.62 3.61 430 5.4 29 25.75 3.46 1597 20 30 26.66 3.34840 10.5 31 27.09 3.29 503 6.3 32 28.06 3.18 424 5.3 33 28.93 3.08 3644.6 34 29.21 3.06 1023 12.8 35 29.93 2.98 486 6.1 36 31.36 2.85 614 7.737 31.85 2.81 220 2.8 38 31.99 2.80 177 2.2 39 32.80 2.73 277 3.5 4033.19 2.70 162 2 41 33.41 2.68 345 4.3 42 33.65 2.66 244 3 43 35.64 2.52178 2.2 44 35.90 2.50 416 5.2 45 36.23 2.48 63 0.8 46 37.02 2.43 96 1.247 37.32 2.41 110 1.4 48 37.75 2.38 130 1.6 49 39.03 2.31 195 2.4 5039.39 2.29 183 2.3

Crystalline Compound 2 was also characterized by PLM which showedparticle size range of 1-50 μm.

Example 14. Preparation and Characterization of Compound 2Microsuspensions

Two Compound 2 microsuspensions were prepared.

1. Preparation and Characterization of 167.27 mg/mL Compound 2Microsuspension

A Compound 2 microsuspension was prepared by wet-milling method. About240 mg of Compound 2 was added to 1 mL of 3% (w/v) TPGS-1% (w/v) HPMC E5in a milling jar. 2 mL of zirconium beads with a diameter of 0.8 mm(YTZ® Grinding Media, Nikkato Co., Japan) were added using a measuringcylinder. The milling jar was placed in a planetaty miller. The millingwas conducted at a rotating speed of 800 rpm for 1 hour in each cycleand the suspension was collected after 3 milling cycles.

The collected suspension was about 0.1-0.2 mL. Large volume loss was dueto sample residual on the milling beads. PLM showed most particles werebelow 5 μm in size. Concentration of Compound 2 in the suspensiondetermined by HPLC was 167.27 mg/mL. The final product was stored in a1.5 mL sealed glass vial at room temperature and protected from lightbefore PK study. Visual inspection of the suspensions showed that theproduct was homogeneous, syringeable and easily resuspendable followingshort-time vortex or water-bath sonication, suitable for intramuscularinjection.

2. Preparation and Characterization of 259.62 mg/mL Compound 2Microsuspension

A Compound 2 microsuspension was prepared by wet-milling method. About1.6 g of Compound 2 was added to 4 mL of 3% (w/v) TPGS-1% (w/v) HPMC E5in a milling jar. 4 mL of zirconium beads with a diameter of 0.8 mm(YTZ® Grinding Media, Nikkato Co., Japan) were added using a measuringcylinder. The milling jar was placed in a planetaty miller. The millingwas conducted at a rotating speed of 800 rpm for 1 hour in each cycleand the suspension was collected after 3 milling cycles.

The collected suspension was About 2.8 mL and most particles werebetween 1 μm and 5 μm in size. Concentration of Compound 2 in thesuspension determined by HPLC was 259.62 mg/mL. The collectedmicrosuspension was stored in a 1.5 mL sealed glass vial at roomtemperature and protected from light before PK study. Visual inspectionof the suspension showed that the product was homogeneous, syringeableand easily resuspendable following short-time vortex or water-bathsonication, suitable for preclinical PK study via intramuscularinjection.

While preferred aspects of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch aspects are provided by way of example only. Numerous variations,changes, and substitutions will now occur to those skilled in the artwithout departing from the invention. It should be understood thatvarious alternatives to the aspects of the invention described hereinmay be employed in practicing the invention. It is intended that thefollowing claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

Embodiments Directed to a Pharmaceutical Suspension ComprisingCrystalline Formula (III) Embodiment 1

A pharmaceutical suspension comprising nanoparticles or microparticlesof a crystalline compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

wherein:

R¹¹ is a lipophilic moiety.

Embodiment 2

The pharmaceutical composition of Embodiment 1, wherein R¹¹ isoptionally substituted C₁-C₃₀alkyl, optionally substitutedC₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl.

Embodiment 3

The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ isoptionally substituted C₁-C₂₀alkyl, optionally substitutedC₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl.

Embodiment 4

The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ isC₁-C₂₀alkyl.

Embodiment 5

The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ isC₁-C₃₀alkyl.

Embodiment 6

The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ isC₁-C₆alkyl.

Embodiment 7

The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ isC₇-C₃₀alkyl.

Embodiment 8

The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ isC₇-C₂₀alkyl.

Embodiment 9

The pharmaceutical composition of any one Embodiments 1-8, wherein R¹¹is

Embodiment 10

The pharmaceutical composition of Embodiment 1 or 2, wherein R¹¹ isC₂-C₃₀alkenyl.

Embodiment 11

The pharmaceutical composition of Embodiment 10, wherein R¹¹ is

Embodiment 12

The pharmaceutical suspension of Embodiment 1, wherein the compound offormula (III) is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Embodiment 13

The pharmaceutical suspension of Embodiment 1, wherein the compound offormula (III) is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Embodiment 14

The pharmaceutical suspension of any one of Embodiments 1-13, whereinthe size of the nanoparticles is between about 50 nm and about 1000 nm.

Embodiment 15

The pharmaceutical suspension of any one of Embodiments 1-14, whereinthe size of the nanoparticles is about 100 nm.

Embodiment 16

The pharmaceutical suspension of any one of Embodiments 1-13, whereinthe size of the microparticles is between about 1 μm and about 10 μm.

Embodiment 17

The pharmaceutical suspension of any one of Embodiments 1-13, whereinthe size of the microparticles is between about 1 μm and about 5 μm.

Embodiment 18

The pharmaceutical suspension of any one of Embodiments 1-17, furthercomprising a pharmaceutically acceptable excipient selected fromsurfactants, solubilizers, emulsifiers, preservatives, isotonicityagents, dispersing agents, wetting agents, fillers, solvents, buffers,stabilizers, lubricants, thickening agents, suspending agents, and anycombinations thereof.

Embodiment 19

The pharmaceutical suspension of any one of Embodiments 1-18, furthercomprising a surfactant.

Embodiment 20

The pharmaceutical suspension of any one of Embodiments 1-19, furthercomprising a suspending agent.

Embodiment 21

The pharmaceutical suspension of any one of Embodiments 1-20, furthercomprising Synperonic® F108, dodecyl sodium sulfate (SLS),D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropylmethylcellulose (HPMC), and any combinations thereof.

Embodiment 22

The pharmaceutical suspension of any one of Embodiments 1-21, furthercomprising D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) andhydroxypropyl methylcellulose (HPMC).

Embodiment 23

The pharmaceutical composition of any one of Embodiments 1-22, whereinthe concentration of the crystalline compound of Formula (III) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof isbetween about 10 mg/mL and about 50 mg/mL.

Embodiment 24

The pharmaceutical suspension of any one of Embodiments 1-23, whereinthe concentration of the crystalline compound of Formula (III) isgreater than about 50 mg/mL.

Embodiment 25

A method for the treatment or prevention of malaria in a subjectcomprising administering to the subject a pharmaceutical suspension ofany one of Embodiments 1-24.

Embodiment 26

The method of Embodiment 25, wherein the pharmaceutical suspension isadministered by subcutaneous or intramuscular injection.

Embodiment 27

The method of Embodiment 25, wherein the pharmaceutical suspension iseffective for sustained or controlled release.

Embodiment 28

The method of any one of Embodiments 25-27, further comprisingadministering an additional antimalarial agent.

Embodiment 29

The method of Embodiment 28, wherein the additional antimalarial agentis selected from artemisinin, artemisinin derivatives, atovaquone,proguanil, quinine, chloroquine, amodiaquine, pyrimethamine,doxycycline, clindamycin, mefloquine, primaquine, pyronaridine,halofantrine, or ELQ-300.

Embodiments Directed to a Pharmaceutical Suspension ComprisingCrystalline Atovaquone Embodiment 1

A pharmaceutical suspension comprising nanoparticles or microparticlesof a crystalline form of atovaquone, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof.

Embodiment 2

The pharmaceutical suspension of Embodiment 1, wherein the crystallineform of atovaquone, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof is atovaquone-Form I or atovaquone-Form II.

Embodiment 3

The pharmaceutical suspension of Embodiment 2, wherein the crystallineform of atovaquone, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, is atovaquone-Form II wherein the crystalline formhas at least one of the following properties:

-   -   (a) an X-Ray powder diffraction (XRPD) pattern substantially the        same as shown in FIG. 25; or    -   (b) an X-ray powder diffraction (XRPD) pattern comprising        characteristic peaks at about 7.0±0.1° 2θ, about 9.3±0.1° 2θ,        about 14.3±0.1° 2θ, about 14.9±0.1° 2θ, about 18.6±0.1° 2θ,        about 19.3±0.1° 2θ, about 20.1±0.1° 2θ, 22.8±0.1° 2θ, 23.4±0.1°        2θ, and 24.4±0.1° 2θ; or

Embodiment 4

The pharmaceutical suspension of Embodiment 3, wherein the crystallineform of atovaquone-Form II has at least one of the following properties:

-   -   (a) a DSC thermogram substantially the same to the one set forth        in FIG. 26A; or    -   (b) a DSC thermogram with an endotherm having a peak at about        219.9° C.

Embodiment 5

The pharmaceutical suspension of any one of Embodiments 1-4, wherein thesize of the nanoparticles is between about 50 nm and about 1000 nm.

Embodiment 6

The pharmaceutical suspension of any one of Embodiments 1-5, wherein thesize of the nanoparticles is about 100 nm.

Embodiment 7

The pharmaceutical suspension of any one of Embodiments 1-4, wherein thesize of the microparticles is between about 1 μm and about 10 μm.

Embodiment 8

The pharmaceutical suspension of any one of Embodiments 1-4, wherein thesize of the microparticles is between about 1 μm and about 5 μm.

Embodiment 9

The pharmaceutical suspension of any one of Embodiments 1-8, furthercomprising a pharmaceutically acceptable excipient selected fromsurfactants, solubilizers, emulsifiers, preservatives, isotonicityagents, dispersing agents, wetting agents, fillers, solvents, buffers,stabilizers, lubricants, thickening agents, suspending agents, and anycombinations thereof.

Embodiment 10

The pharmaceutical suspension of any one of Embodiments 1-9, furthercomprising a surfactant.

Embodiment 11

The pharmaceutical suspension of any one of Embodiments 1-10, furthercomprising a suspending agent.

Embodiment 12

The pharmaceutical suspension of any one of Embodiments 1-11, furthercomprising Synperonic® F108, dodecyl sodium sulfate (SLS),D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropylmethylcellulose (HPMC), and any combinations thereof.

Embodiment 13

The pharmaceutical suspension of any one of Embodiments 1-12, furthercomprising D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) andhydroxypropyl methylcellulose (HPMC).

Embodiment 14

The pharmaceutical composition of any one of Embodiments 1-13, whereinthe concentration of the crystalline atovaquone or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof is between about 10mg/mL and about 50 mg/mL.

Embodiment 15

The pharmaceutical suspension of any one of Embodiments 1-13, whereinthe concentration of the crystalline atovaquone is greater than about 50mg/mL.

Embodiment 16

A method for the treatment or prevention of malaria in a subjectcomprising administering to the subject a pharmaceutical suspension ofany one of Embodiments 1-15.

Embodiment 17

The method of Embodiment 16, wherein the pharmaceutical suspension isadministered by subcutaneous or intramuscular injection.

Embodiment 18

The method of Embodiment 17, wherein the pharmaceutical suspension iseffective for sustained or controlled release.

Embodiment 19

The method of any one of Embodiments 10-18, further comprisingadministering an additional antimalarial agent.

Embodiment 20

The method of Embodiment 19, wherein the additional antimalarial agentis selected from artemisinin, artemisinin derivatives, atovaquone,proguanil, quinine, chloroquine, amodiaquine, pyrimethamine,doxycycline, clindamycin, mefloquine, primaquine, pyronaridine,halofantrine, or ELQ-300.

Embodiments Directed to a Pharmaceutical Suspension ComprisingCrystalline Pyronaridine Embodiment 1

A pharmaceutical suspension comprising nanoparticles or microparticlesof a crystalline form of pyronaridine, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof.

Embodiment 2

The pharmaceutical suspension of Embodiment 1, wherein thepharmaceutical acceptable salt of pyronaridine is pyronaridine pamoate,pyronaridine benzenesulfonate, pyronaridine palmitate, or pyronaridinenaphthalate.

Embodiment 3

The pharmaceutical suspension of Embodiment 1 or 2, wherein thecrystalline form of pyronaridine, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof is pyronaridine-Form I,pyronaridine-Form II, pyronaridine-Form III, pyronaridine-Form IV, orpyronaridine-Form V.

Embodiment 4

The pharmaceutical suspension of any one of Embodiment 1-3, wherein thesize of the nanoparticles is between about 50 nm and about 1000 nm.

Embodiment 5

The pharmaceutical suspension of any one of Embodiment 1-4, wherein thesize of the nanoparticles is about 100 nm.

Embodiment 6

The pharmaceutical suspension of any one of Embodiments 1-3, wherein thesize of the microparticles is between about 1 μm and about 10 μm.

Embodiment 7

The pharmaceutical suspension of any one of Embodiments 1-3, wherein thesize of the microparticles is between about 1 μm and about 5 μm.

Embodiment 8

The pharmaceutical suspension of any one of Embodiments 1-7, furthercomprising a pharmaceutically acceptable excipient selected fromsurfactants, solubilizers, emulsifiers, preservatives, isotonicityagents, dispersing agents, wetting agents, fillers, solvents, buffers,stabilizers, lubricants, thickening agents, suspending agents, and anycombinations thereof.

Embodiment 9

The pharmaceutical suspension of any one of Embodiments 1-8, furthercomprising a surfactant.

Embodiment 10

The pharmaceutical suspension of any one of Embodiments 1-9, furthercomprising a suspending agent.

Embodiment 11

The pharmaceutical suspension of any one of Embodiments 1-10, furthercomprising Synperonic® F108, dodecyl sodium sulfate (SLS),D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropylmethylcellulose (HPMC), and any combinations thereof.

Embodiment 12

The pharmaceutical suspension of any one of Embodiments 1-11, furthercomprising D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) andhydroxypropyl methylcellulose (HPMC).

Embodiment 13

The pharmaceutical composition of any one of Embodiments 1-12, whereinthe concentration of the crystalline pyronaridine or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof is between about 10mg/mL and about 50 mg/mL.

Embodiment 14

The pharmaceutical suspension of any one of Embodiments 1-13, whereinthe concentration of the crystalline pyronaridine is greater than about50 mg/mL.

Embodiment 15

A method for the treatment or prevention of malaria in a subjectcomprising administering to the subject a pharmaceutical suspension ofany one of Embodiments 1-14.

Embodiment 16

The method of Embodiment 15, wherein the pharmaceutical suspension isadministered by subcutaneous or intramuscular injection.

Embodiment 17

The method of Embodiment 15, wherein the pharmaceutical suspension iseffective for sustained or controlled release.

Embodiment 18

The method of any one of Embodiments 15-17, further comprisingadministering an additional antimalarial agent.

Embodiment 19

The method of Embodiment 18, wherein the additional antimalarial agentis selected from artemisinin, artemisinin derivatives, atovaquone,proguanil, quinine, chloroquine, amodiaquine, pyrimethamine,doxycycline, clindamycin, mefloquine, primaquine, pyronaridine,halofantrine, or ELQ-300.

Embodiments Directed to a Pharmaceutical Composition Comprising aCrystalline ELQ-300 Embodiment 1

A pharmaceutical suspension comprising nanoparticles or microparticlesof a crystalline form of ELQ-300, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof.

Embodiment 2

The pharmaceutical suspension of Embodiment 1, wherein the crystallineform of ELQ-300, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof is ELQ-300-Form IA, ELQ-300-Form IB, ELQ-300-FormII, ELQ-300-Form III, ELQ-300-Form IV, or ELQ-300-Form V.

Embodiment 3

The pharmaceutical suspension of Embodiment 2, wherein the crystallineform of ELQ-300, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, is ELQ-300-Form II wherein the crystalline formhas at least one of the following properties:

-   -   (a) an X-Ray powder diffraction (XRPD) pattern substantially the        same as shown in FIG. 9; or    -   (b) an X-ray powder diffraction (XRPD) pattern comprising        characteristic peaks at about 7.6±0.1° 2θ, about 12.7±0.1° 2θ,        about 20.4±0.1° 2θ, about 23.0±0.1° 2θ, about 25.6±0.1° 2θ,        about 28.2±0.1° 2θ, about 30.8±0.1° 2θ, about 33.5±0.1° 2θ,        about 36.1° 2θ, and about 38.8±0.1° 2θ.

Embodiment 4

The pharmaceutical suspension of Embodiment 3, wherein the crystallineform of ELQ-300-Form II has at least one of the following properties:

-   -   (a) a DSC thermogram substantially the same to the one set forth        in FIG. 11; or    -   (b) a DSC thermogram with an endotherm having a peak at about        297.5° C.

Embodiment 5

The pharmaceutical suspension of any one of Embodiments 1-4, wherein thesize of the nanoparticles is between about 50 nm and about 1000 nm.

Embodiment 6

The pharmaceutical suspension of any one of Embodiments 1-5, wherein thesize of the nanoparticles is about 100 nm.

Embodiment 7

The pharmaceutical suspension of any one of Embodiments 1-4, wherein thesize of the microparticles is between about 1 μm and about 10 μm.

Embodiment 8

The pharmaceutical suspension of any one of Embodiments 1-4, wherein thesize of the microparticles is between about 1 μm and about 5 μm.

Embodiment 9

The pharmaceutical suspension of any one of Embodiments 1-8, furthercomprising a pharmaceutically acceptable excipient selected fromsurfactants, solubilizers, emulsifiers, preservatives, isotonicityagents, dispersing agents, wetting agents, fillers, solvents, buffers,stabilizers, lubricants, thickening agents, suspending agents, and anycombinations thereof.

Embodiment 10

The pharmaceutical suspension of any one of Embodiments 1-9, furthercomprising a surfactant.

Embodiment 11

The pharmaceutical suspension of any one of Embodiments 1-10, furthercomprising a suspending agent.

Embodiment 12

The pharmaceutical suspension of any one of Embodiments 1-11, furthercomprising Synperonic® F108, dodecyl sodium sulfate (SLS),D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropylmethylcellulose (HPMC), and any combinations thereof.

Embodiment 13

The pharmaceutical suspension of any one of Embodiments 1-12, furthercomprising D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) andhydroxypropyl methylcellulose (HPMC).

Embodiment 14

The pharmaceutical suspension of any one of Embodiments 1-12, furthercomprising D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS).

Embodiment 15

The pharmaceutical suspension of any one of Embodiments 1-12, furthercomprising Synperonic® F108.

Embodiment 16

The pharmaceutical composition of any one of Embodiments 1-15, whereinthe concentration of the crystalline ELQ-300 or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof is between about 10mg/mL and about 50 mg/mL.

Embodiment 17

The pharmaceutical suspension of any one of Embodiments 1-15, whereinthe concentration of the crystalline ELQ-300 is greater than about 50mg/mL.

Embodiment 18

A method for the treatment or prevention of malaria in a subjectcomprising administering to the subject a pharmaceutical suspension ofany one of Embodiments 1-17.

Embodiment 19

The method of Embodiment 18, wherein the pharmaceutical suspension isadministered by subcutaneous or intramuscular injection.

Embodiment 20

The method of Embodiment 19, wherein the pharmaceutical suspension iseffective for sustained or controlled release.

Embodiment 21

The method of any one of Embodiments 18-20, further comprisingadministering an additional antimalarial agent.

Embodiment 22

The method of Embodiment 21, wherein the additional antimalarial agentis selected from artemisinin, artemisinin derivatives, atovaquone,proguanil, quinine, chloroquine, amodiaquine, pyrimethamine,doxycycline, clindamycin, mefloquine, primaquine, pyronaridine,halofantrine, or ELQ-300.

Embodiments Directed to a Compound of Formula (I) Embodiment 1

A compound of Formula (I) or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof:

wherein

-   -   R is —C(R^(1a))₂OC(═O)R¹, —R², —C(═O)OR³, or C(═O)R⁴;    -   R¹ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, optionally substituted C₂-C₃₀alkynyl, optionally        substituted C₃-C₅cycloalkyl, or optionally substituted        C₂-C₈heterocycloalkyl;    -   each R^(1a) is independently hydrogen, halogen, or optionally        substituted C₁-C₆alkyl;    -   or two R^(1a) are taken together with the carbon atom to which        they are attached to form an optionally substituted        C₃-C₈cycloalkyl;    -   R² is optionally substituted (C₁-C₆alkylene)aryl, optionally        substituted (C₁-C₆alkylene)heteroaryl, optionally substituted        (C₁-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted        (C₁-C₆alkylene)C₂-C₈heterocycloalkyl;    -   R³ is optionally substituted C₅-C₃₀alkyl, optionally substituted        C₄-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl; and    -   R⁴ is optionally substituted C₅-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl.

Embodiment 2

The compound of Embodiment 1, wherein R is —C(R^(1a))₂OC(═O)R¹.

Embodiment 3

The compound of Embodiment 1 or 2, wherein each R^(1a) is hydrogen.

Embodiment 4

The compound of any one of Embodiments 1-3, wherein R¹ is optionallysubstituted C₁-C₂₀alkyl or optionally substituted C₂-C₃₀alkenyl.

Embodiment 5

The compound of any one of Embodiments 1-4, wherein R¹ is C₁-C₆alkyl.

Embodiment 6

The compound of any one of Embodiments 1-4, wherein R¹ is C₇-C₂₀alkyl.

Embodiment 7

The compound of any one of Embodiments 1-4, wherein R¹ is

Embodiment 8

The compound of any one of Embodiments 1-4, wherein R¹ is

Embodiment 9

The compound of any one of Embodiments 1-3, wherein R¹ is C₂-C₃₀alkenyl.

Embodiment 10

The compound of Embodiment 9, wherein R¹ is C₂-C₆alkenyl.

Embodiment 11

The compound of Embodiment 9, wherein R¹ is C₇-C₃₀alkenyl.

Embodiment 12

The compound of Embodiment 9, wherein R¹ is

Embodiment 13

The compound of Embodiment 1, wherein R is —C(═O)OR³.

Embodiment 14

The compound of Embodiment 13, wherein R³ is C₅-C₂₀alkyl.

Embodiment 15

The compound of Embodiment 14, wherein R³ is C₅-C₁₀alkyl.

Embodiment 16

The compound of Embodiment 14, wherein R³ is C₁₁-C₂₀alkyl.

Embodiment 17

The compound of Embodiment 14, wherein R³ is

Embodiment 18

The compound of Embodiment 1, wherein R is —C(═O)R⁴.

Embodiment 19

The compound of Embodiment 18, wherein R⁴ is C₅-C₂₀alkyl.

Embodiment 20

The compound of Embodiment 18, wherein R⁴ is C₁-C₂₀alkyl.

Embodiment 21

The compound of Embodiment 18, wherein R⁴ is C₁₁-C₂₀alkyl.

Embodiments Directed to Crystalline Form of((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate Embodiment 1

A crystalline form of((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Embodiment 2

The crystalline form of Embodiment 1, wherein the crystalline form of((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate has at least one of the following properties:

-   -   (a) an X-Ray powder diffraction (XRPD) pattern substantially the        same as shown in FIG. 41; or    -   (b) an X-ray powder diffraction (XRPD) pattern comprising        characteristic peaks at about 14.4±0.1° 2θ, about 15.1±0.1° 2θ,        about 17.7±0.1° 2θ, about 18.1±0.1° 2θ, about 22.3±0.1° 2θ, and        about 22.6±0.1° 2θ; or    -   (c) a DSC thermogram substantially the same to the one set forth        in FIG. 42A; or    -   (d) a DSC thermogram with an endotherm having a peak at about        99.5° C.

Embodiment 3

The crystalline form of Embodiment 2, wherein the X-ray powderdiffraction (XRPD) pattern further comprises characteristic peaks atabout 19.1°±0.1° 2θ, about 20.30±0.1° 2θ, about 21.2°±0.1° 2θ, about26.7°±0.1° 2θ, and about 29.21°±0.1° 2θ.

Embodiments Directed to a Pharmaceutical Composition Comprising aCompound of Formula (II) Embodiment 1

A pharmaceutical composition comprising:

-   -   (i) an oil; and    -   (ii) a compound of Formula (II) or a pharmaceutically acceptable        salt, solvate, or stereoisomer thereof:

wherein:

-   -   R′ is —C(R^(7a))₂OC(═O)R⁷, —R⁸, —C(═O)OR⁹, or —C(═O)R¹⁰;    -   R⁷ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, optionally substituted C₂-C₃₀alkynyl, optionally        substituted C₃-C₈cycloalkyl, or optionally substituted        C₂-C₈heterocycloalkyl;    -   each R^(7a) is independently hydrogen, halogen, or optionally        substituted C₁-C₆alkyl;    -   or two R^(7a) are taken together with the carbon atom to which        they are attached to form an optionally substituted        C₃-C₈cycloalkyl;    -   R⁸ is optionally substituted (C₁-C₆alkylene)aryl, optionally        substituted (C₁-C₆alkylene)heteroaryl, optionally substituted        (C₁-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted        (C₁-C₆alkylene)C₂-C₈heterocycloalkyl;    -   R⁹ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl; and    -   R¹⁰ is optionally substituted C₁-C₃₀alkyl, optionally        substituted C₂-C₃₀alkenyl, or optionally substituted        C₂-C₃₀alkynyl.

Embodiment 2

The pharmaceutical composition of Embodiment 1, wherein R′ is—C(R^(7a))₂OC(═)R⁷.

Embodiment 3

The pharmaceutical composition of Embodiment 1 or 2, wherein each R^(7a)is hydrogen.

Embodiment 4

The pharmaceutical composition of any one of Embodiment 1-3, wherein R⁷is optionally substituted C₁-C₂₀alkyl or optionally substitutedC₂-C₃₀alkenyl.

Embodiment 5

The pharmaceutical composition of any one of Embodiments 1-4, wherein R⁷is C₁-C₆alkyl.

Embodiment 6

The pharmaceutical composition of any one of Embodiments 1-4, wherein R⁷is C₇-C₂₀alkyl.

Embodiment 7

The pharmaceutical composition of any one of Embodiments 1-4, wherein R⁷is

Embodiment 8

The pharmaceutical composition of any one of Embodiments 1-4, wherein R⁷is

Embodiment 9

The pharmaceutical composition of any one of Embodiment 1-4, wherein R⁷is C₂-C₃₀alkenyl.

Embodiment 10

The pharmaceutical composition of Embodiment 9, wherein R⁷ isC₂-C₆alkenyl.

Embodiment 11

The pharmaceutical composition of Embodiment 9, wherein R⁷ isC₇-C₃₀alkenyl.

Embodiment 12

The pharmaceutical composition of Embodiment 9 or 11, wherein R⁷ is

Embodiment 13

The pharmaceutical composition of Embodiment 1, wherein R′ is —C(═O)OR⁹.

Embodiment 14

The pharmaceutical composition of Embodiment 13, wherein R⁹ isoptionally substituted C₅-C₃₀alkyl, optionally substitutedC₄-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl.

Embodiment 15

The pharmaceutical composition of Embodiment 13, wherein R⁹ isC₁-C₆alkyl.

Embodiment 16

The pharmaceutical composition of Embodiment 13, wherein R⁹ isC₇-C₂₀alkyl.

Embodiment 17

The pharmaceutical composition of Embodiment 13, wherein R⁹ isC₅-C₂₀alkyl.

Embodiment 18

The pharmaceutical composition of Embodiment 13, wherein R⁹ isC₅-C₁₀alkyl.

Embodiment 19

The pharmaceutical composition of Embodiment 13, wherein R⁹ isC₁₁-C₂₀alkyl.

Embodiment 20

The pharmaceutical composition of Embodiment 13, wherein R⁹ is

Embodiment 21

The pharmaceutical composition of Embodiment 1, wherein R′ is —C(═O)R¹⁰.

Embodiment 22

The pharmaceutical composition of Embodiment 21, wherein R¹⁰ isoptionally substituted C₅-C₃₀alkyl, optionally substitutedC₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl.

Embodiment 23

The pharmaceutical composition of Embodiment 21, wherein R¹⁰ isC₁-C₆alkyl.

Embodiment 24

The pharmaceutical composition of Embodiment 21, wherein R¹⁰ isC₇-C₂₀alkyl.

Embodiment 25

The pharmaceutical composition of Embodiment 21, wherein R¹⁰ isC₅-C₂₀alkyl.

Embodiment 26

The pharmaceutical composition of Embodiment 21, wherein R¹⁰ isC₅-C₁₀alkyl.

Embodiment 27

The pharmaceutical composition of Embodiment 21, wherein R¹⁰ isC₁₁-C₂₀alkyl.

Embodiment 28

The pharmaceutical composition of any one of Embodiments 1-27, whereinthe oil is a vegetable oil.

Embodiment 29

The pharmaceutical composition of any one of Embodiments 1-28, whereinthe oil is selected from corn oil, peanut oil, sesame oil, olive oil,palm oil, safflower oil, soybean oil, cottonseed oil, rapeseed oil,sunflower oil and mixtures thereof.

Embodiment 30

The pharmaceutical composition of Embodiments 1-29, wherein the oil issesame oil.

Embodiment 31

The pharmaceutical composition of any one of Embodiments 1-30, whereinthe concentration of the compound of Formula (II) or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof is greater than about50 mg/mL.

Embodiments Directed to a Pharmaceutical Suspension ComprisingCrystalline Formula (II) Embodiment 1

A pharmaceutical suspension comprising nanoparticles or microparticlesof a crystalline compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   R′ is —C(R^(7a))₂OC(═O)R⁷, —R, —C(═O)OR⁹, or —C(═O)R¹⁰;    -   R⁷ is optionally substituted C₁-C₃₀alkyl, optionally substituted        C₂-C₃₀alkenyl, optionally substituted C₂-C₃₀alkynyl, optionally        substituted C₃-C₈cycloalkyl, or optionally substituted        C₂-C₈heterocycloalkyl;    -   each R^(7a) is independently hydrogen, halogen, or optionally        substituted C₁-C₆alkyl;    -   or two R^(7a) are taken together with the carbon atom to which        they are attached to form an optionally substituted        C₃-C₈cycloalkyl;    -   R⁸ is optionally substituted (C₁-C₆alkylene)aryl, optionally        substituted (C₁-C₆alkylene)heteroaryl, optionally substituted        (C₁-C₆alkylene)C₃-C₈cycloalkyl, or optionally substituted        (C₁-C₆alkylene)C₂-C₈heterocycloalkyl;    -   R⁹ is optionally substituted C₁-C₂₀alkyl, optionally substituted        C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl; and    -   R¹⁰ is optionally substituted C₁-C₂₀alkyl, optionally        substituted C₂-C₂₀alkenyl, or optionally substituted        C₂-C₂₀alkynyl.

Embodiment 2

The pharmaceutical suspension of Embodiment 1, wherein R′ is—C(R^(7a))₂OC(═O)R⁷.

Embodiment 3

The pharmaceutical suspension of Embodiment 1 or 2, wherein each R^(7a)is hydrogen.

Embodiment 4

The pharmaceutical suspension of any one of Embodiment 1-3, wherein R⁷is optionally substituted C₁-C₂₀alkyl or optionally substitutedC₂-C₃₀alkenyl.

Embodiment 5

The pharmaceutical suspension of any one of Embodiments 1-3, wherein R⁷is C₁-C₆alkyl.

Embodiment 6

The pharmaceutical suspension of any one of Embodiments 1-3, wherein R⁷is C₇-C₂₀alkyl.

Embodiment 7

The pharmaceutical suspension of any one of Embodiments 1-3, wherein R⁷is

Embodiment 8

The pharmaceutical suspension of any one of Embodiments 1-3, wherein R⁷is

Embodiment 9

The pharmaceutical suspension of any one of Embodiment 1-3, wherein R⁷is C₂-C₃₀alkenyl.

Embodiment 10

The pharmaceutical suspension of Embodiment 9, wherein R⁷ isC₂-C₆alkenyl.

Embodiment 11

The pharmaceutical suspension of Embodiment 9, wherein R⁷ isC₇-C₃₀alkenyl.

Embodiment 12

The pharmaceutical suspension of any one of Embodiments 9, wherein R⁷ is

Embodiment 13

The pharmaceutical suspension of Embodiment 1, wherein R′ is —C(═O)OR⁹.

Embodiment 14

The pharmaceutical suspension of Embodiment 13, wherein R⁹ is optionallysubstituted C₅-C₃₀alkyl, optionally substituted C₄-C₃₀alkenyl, oroptionally substituted C₂-C₃₀alkynyl.

Embodiment 15

The pharmaceutical suspension of Embodiment 13, wherein R⁹ isC₁-C₆alkyl.

Embodiment 16

The pharmaceutical suspension of Embodiment 13, wherein R⁹ isC₇-C₂₀alkyl.

Embodiment 17

The pharmaceutical suspension of Embodiment 13, wherein R⁹ isC₅-C₂₀alkyl.

Embodiment 18

The pharmaceutical suspension of Embodiment 13, wherein R⁹ isC₅-C₁₀alkyl.

Embodiment 19

The pharmaceutical suspension of Embodiment 13, wherein R⁹ isC₁₁-C₂₀alkyl.

Embodiment 20

The pharmaceutical suspension of Embodiment 13, wherein R⁹ is

Embodiment 21

The pharmaceutical suspension of Embodiment 1, wherein R′ is —C(═O)R¹⁰.

Embodiment 22

The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ isoptionally substituted C₅-C₃₀alkyl, optionally substitutedC₂-C₃₀alkenyl, or optionally substituted C₂-C₃₀alkynyl.

Embodiment 23

The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ isC₁-C₆alkyl.

Embodiment 24

The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ isC₇-C₂₀alkyl.

Embodiment 25

The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ isC₅-C₂₀alkyl.

Embodiment 26

The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ isC₅-C₁₀alkyl.

Embodiment 27

The pharmaceutical suspension of Embodiment 21, wherein R¹⁰ isC₁₁-C₂₀alkyl.

Embodiment 28

The pharmaceutical suspension of Embodiment 21, wherein the compound offormula (II) is((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof.

Embodiment 29

The pharmaceutical suspension of Embodiment 28, wherein the crystalline((6-chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)oxy)methylbutyrate has at least one of the following properties:

-   -   (a) an X-Ray powder diffraction (XRPD) pattern substantially the        same as shown in FIG. 41; or    -   (b) an X-ray powder diffraction (XRPD) pattern comprising        characteristic peaks at about 14.4±0.1° 2θ, about 15.1±0.1° 2θ,        about 17.7±0.1° 2θ, about 18.1±0.1° 2θ, about 22.3±0.1° 2θ, and        about 22.6±0.1° 2θ; or    -   (c) a DSC thermogram substantially the same to the one set forth        in FIG. 42A; or    -   (d) a DSC thermogram with an endotherm having a peak at about        99.5° C.

Embodiment 30

The pharmaceutical suspension of Embodiment 29, wherein the X-ray powderdiffraction (XRPD) pattern further comprises characteristic peaks atabout 19.1°±0.1° 2θ, about 20.3°±0.1° 2θ, about 21.2°±0.1° 2θ, about26.7°±0.1° 2θ, and about 29.2°±0.1° 2θ.

Embodiment 31

The pharmaceutical suspension of any one of Embodiments 1-30, whereinthe size of the microparticles is between about 1 μm and about 10 μm.

Embodiment 32

The pharmaceutical suspension of any one of Embodiments 1-31, whereinthe size of the microparticles is between about 1 μm and about 5 μm.

Embodiment 33

The pharmaceutical suspension of any one of Embodiments 1-32, furthercomprising a pharmaceutically acceptable excipient selected fromsurfactants, solubilizers, emulsifiers, preservatives, isotonicityagents, dispersing agents, wetting agents, fillers, solvents, buffers,stabilizers, lubricants, thickening agents, suspending agents, and anycombinations thereof.

Embodiment 34

The pharmaceutical suspension of any one of Embodiments 1-33, furthercomprising a surfactant.

Embodiment 35

The pharmaceutical suspension of any one of Embodiments 1-34, furthercomprising a suspending agent.

Embodiment 36

The pharmaceutical suspension of any one of Embodiments 1-35, furthercomprising Synperonic® F108, dodecyl sodium sulfate (SLS),D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), hydroxypropylmethylcellulose (HPMC), and any combinations thereof.

Embodiment 37

The pharmaceutical suspension of any one of Embodiments 1-36, furthercomprising D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) andhydroxypropyl methylcellulose (HPMC).

Embodiment 38

The pharmaceutical composition of any one of Embodiments 1-37, whereinthe concentration of the crystalline compound of Formula (II) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof isbetween about 10 mg/mL and about 50 mg/mL.

Embodiment 39

The pharmaceutical suspension of any one of Embodiments 1-38, whereinthe concentration of the crystalline compound of Formula (II) is greaterthan about 50 mg/mL.

We claim:
 1. A compound of Formula (IV) or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof:

wherein R²¹ is optionally substituted C₃-C₃₀alkenyl or optionallysubstituted C₂-C₃₀alkynyl.
 2. The compound of claim 1, wherein R²¹ isC₃-C₃₀alkenyl.
 3. The compound of claim 1, wherein R²¹ is C₆-C₃₀alkenyl.4. The compound of claim 1, wherein R²¹ is C₆-C₂₅alkenyl.
 5. Thecompound of claim 1, wherein R²¹ is C₁₅-C₂₅alkenyl.


6. The compound of claim 1, wherein R²¹ is.
 7. A pharmaceuticalcomposition comprising: (i) an oil; and (ii) a compound of Formula (III)or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein: R¹¹ is a lipophilic moiety.
 8. The pharmaceutical compositionof claim 7, wherein R¹¹ is optionally substituted C₁-C₃₀alkyl,optionally substituted C₂-C₃₀alkenyl, or optionally substitutedC₂-C₃₀alkynyl.
 9. The pharmaceutical composition of claim 7 or 8,wherein R¹¹ is optionally substituted C₁-C₂₀alkyl, optionallysubstituted C₂-C₂₀alkenyl, or optionally substituted C₂-C₂₀alkynyl. 10.The pharmaceutical composition of claim 7 or 8, wherein R¹¹ isC₁-C₆alkyl.
 11. The pharmaceutical composition of claim 7 or 8, whereinR¹¹ is C₇-C₃₀alkyl.
 12. The pharmaceutical composition of any one claim7 or 8, wherein R¹¹ is


13. The pharmaceutical composition of claim 7 or 8, wherein R¹¹ isC₂-C₃₀alkenyl.
 14. The pharmaceutical composition of claim 13, whereinR¹¹ is C₃-C₃₀alkenyl.
 15. The pharmaceutical composition of claim 13,wherein R¹¹ is C₆-C₃₀alkenyl.
 16. The pharmaceutical composition ofclaim 13, wherein R¹¹ is C₆-C₂₅alkenyl.
 17. The pharmaceuticalcomposition of claim 13, wherein R¹¹ is C₁₅-C₂₅alkenyl.
 18. Thepharmaceutical composition of claim 13, wherein R¹¹ is


19. The pharmaceutical composition of any one of claims 7-18, whereinthe oil is a vegetable oil.
 20. The pharmaceutical composition of anyone of claims 7-19, wherein the oil is selected from corn oil, peanutoil, sesame oil, olive oil, palm oil, safflower oil, soybean oil,cottonseed oil, rapeseed oil, sunflower oil and mixtures thereof. 21.The pharmaceutical composition of any one of claims 7-20, wherein theoil is sesame oil.
 22. The pharmaceutical composition of any one ofclaims 7-21, wherein the concentration of the compound of Formula (III)or a pharmaceutically acceptable salt, solvate, or stereoisomer thereofis greater than about 50 mg/mL.
 23. The pharmaceutical composition ofany one of claims 7-22, wherein the concentration of the compound ofFormula (III) or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof is greater than about 100 mg/mL.
 24. Thepharmaceutical composition of any one of claims 7-22, wherein theconcentration of the compound of Formula (III) or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof is greater than about200 mg/mL.
 25. A method for the treatment or prevention of malaria in asubject comprising administering to the subject a compound of any one ofclaims 1-6 or a pharmaceutical composition of any one of claims 7-24.26. The method of claim 25, wherein the pharmaceutical composition isadministered by subcutaneous or intramuscular injection.
 27. The methodof claim 25 or 26, wherein the pharmaceutical composition is effectivefor sustained or controlled release.
 28. The method of any one of claims25-27, wherein the compound of Formula (III) or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, comprised in thepharmaceutical composition of any one of claims 7-24 is administered ata dose of about 5 to about 20 mg/day.
 29. The method of any one ofclaims 25-28, wherein the compound of Formula (III) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,comprised in the pharmaceutical composition of any one of claims 7-24 isreleased from the pharmaceutical composition over a period of a minimumof about 30 days after administration.
 30. The method of any one ofclaims 25-29, wherein the compound of Formula (III) or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,comprised in the pharmaceutical composition of any one of claim 7-24 isreleased from the pharmaceutical composition at a rate providing anaverage concentration oftrans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione inthe blood plasma of said subject of at least about 1000 nM over about 13weeks.
 31. The method of any one of claims 25-30, further comprisingadministering an additional antimalarial agent.
 32. The method of claim31, wherein the additional antimalarial agent is selected fromartemisinin, artemisinin derivatives, atovaquone, proguanil, quinine,chloroquine, amodiaquine, pyrimethamine, doxycycline, clindamycin,mefloquine, primaquine, pyronaridine, halofantrine, or ELQ-300.
 33. Amethod of killing or inhibiting the growth of a Plasmodium speciescomprising contacting the species with an effective amount of a compoundof any one of claims 1-6.
 34. The method of claim 33, wherein thePlasmodium species is Plasmodium falciparum, Plasmodium vivax,Plasmodium ovale, Plasmodium malariae, or Plasmodium knowlesi.